INFLAMMATION 
AN ARTICLE BY J. G. ADAMI, 
M.A., M.D., REPRINTED FROM 
PROF. CLIFFORD ALLBUTT’S 
NEW SYSTEM OF MEDICINE 
FOR PRIVATE CIRCULATION 
THE MACMILLAN COMPANY 
NEW YORK 
1896 MACMILLAN AND CO. 
Copyright, 1896, 
Nortoonlr IfJress 
J. S. Cushing & Co. Berwick & Smith 
Norwood Mass. TJ.S.A. PREFACE 
Believing that it will be advantageous to the students attend- 
ing my course to be able to obtain for themselves this study or 
essay upon Inflammation, I have begged the publishers of Professor 
Allbutt’s New System of Medicine to grant me reprints, especially 
for the use of McGill students. I would here record my apprecia- 
tion of the favour shown to me by The Macmillan Company in 
departing from ordinary usage and acceding so willingly to my 
request. 
J. GEOEGE ADAMI. 
McGill University, September, 1896. 
Pathological Laboratory, INFLAMMATION1 
Part I.—A General Survey of the Process op Inflammation 
Chapter 1. Introduction. Chapter 2. The Comparative Pathology of Inflamma- 
tion. Chapter 3. The Main Forms of the Process of Acute Inflammation in the 
Higher Animals. 
Chapter 1. On the Part played by the Leucocytes. Chapter 2. On the Inflamma- 
tory Exudation.—Chapters. On the Part played by the Blood-Vessels. Chap- 
ter 4. On the Passage of Corpuscles out of the Vessels. Chapter 5. On the Part 
played by the Nervous System.—Chapter 6. On the Part played by the Cells of 
the Tissue. Chapter 7. On Fibrous Hyperplasia and its Kelationship to Inflam- 
mation. 
Part 11. The Factors in the Inflammatory Process 
Part HI 
Chapter 1. On Classification.—Chapter 2. On Systemic Changes accompanying 
Local Injury and Inflammation. Chapter 3. Conclusion. Bibliography. 
PART I. A General Survey oe the Process of Inflammation 
Chapter 1. Introduction 
Definition of Inflammation. —lt is usual to begin the description of 
a morbid process by defining that process. In the case of inflamma- 
1 The following article is an attempt to bring into order the very numerous recent 
researches upon the inflammatory process, and to show#whither they appear to tend; it 
pretends in no wise to be a complete treatise upon the development of our knowledge of 
the subject. Space alone has forbidden that I should trace the full history. I would 
therefore strongly urge that as a corrective other works he consulted in which the earlier 
theories are treated at length; more especially would I recommend (as throwing light 
upon the progress of our knowledge) Professor Burdon-Sandersou’s article upon Inflam- 
mation in Holmes’s System of Surgery. INFLAMMA TION 
55 
tion, however, we have to deal with a process so complex, so modified by 
modifications of the many factors involved, and so variable in its manifes- 
tations according to the variety of its causes and the region of incidence, 
that the attempt to define it has proved a pitfall to pathologist after 
pathologist; moreover, to advance a definition of the process at the begin- 
ning of this article in terms differing to any considerable extent from 
those employed by previous writers, would demand a criticism of the many 
previous attempts; and in order that the definition put forward be duly 
supported, would necessitate an essay covering the whole field about to 
be traversed. I shall then leave definition to the end, until I have 
marshalled my facts, and have brought into line all that appears to me 
necessary for a correct understanding of the process. The definition 
must be the summing up of the subject, not the introduction thereto. 
Use of the Name.—Yet, in the meantime, inasmuch as divergent 
views are held of the limitations of the use of the name inflammation, 
a few words of introduction are advisable. 
Two courses are before us; either to employ the name strictly in 
accordance with the primitive definition, and thus only to include as 
cases of inflammation those states in which there are present redness, 
swelling, heat and pain, rigidly excluding all cases in which these cardinal 
symptoms are not present; or, on the other hand, departing from 
tradition, to include as inflammations all those morbid processes which 
seem to have a cause and progress inseparable from and merging 
into the cause and progress of the state characterised by the classical 
symptoms. The first course is impossible; it is as though one were to 
declare that red phosphorus is not phosphorus because in externals 
generally it does not agree with the definition of the yellow form made 
years before the allotropic modification was discovered. We are now 
well agreed that of the classical symptoms, one, two or three may be 
unrecognisable, and in fact absent; and yet the condition of inflamma- 
tion be undoubtedly present.1 
The second is the only possible course, that, namely, which associates 
all those states which under suitable conditions may result in the pro- 
duction of the four classical symptoms, and moreover originate from a 
common cause. Holding this view, it will in the meantime be well for 
me, in order to afford a starting-point for the description and discus- 
sion of the subject, to select from the many definitions one which is 
based not on symptomatology, but upon setiology, and indicates a common 
origin for all cases of inflammation. I would select that which in this 
country has received the most cordial support, the definition given by 
Professor Burdon-Sanderson in his well-known article in Holmes’s System 
of Surgery: “ The process of inflammation is the succession of changes 
1 A course allied to this has found favour of late years among sundry surgical patholo- 
gists, who would limit the use of the terra to those cases and those only in which the classi- 
cal symptoms, or the majority thereof, are present and associated with suppuration,— they 
urge with Hiiter that inflammation only occurs when pyogenic micro-organisms are present, 
and state that when a wound heals aseptically it heals without inflammation. This modi- 
fied course is equally impossible; pyogeuesis must not be confounded with inflammation. 56 
SYSTEM OF MEDICINE 
which occurs in a living tissue when it is injured, provided that the injury 
is not of such a degree as at once to destroy its structure and vitality.” 
This definition includes too much. The haemorrhage that occurs in 
the liver when it is injured, and the changes that there occur in the 
extravasated red corpuscles, are scarcely to he classed among inflam- 
matory phenomena; the atrophic changes which occur in the retina, when 
through injury it becomes detached, are due mainly to malposition 
and disuse rather than to the primary trauma. But, as Dr. Burdon 
Sanderson has pointed out, the definition has this great advantage, 
that stating the cause, it clearly recognises inflammation as a process 
and not as a state. The external manifestations of this process under 
favourable conditions—where the region injured is a loose and vascular 
tissue, and where the injury is sufficiently severe or extensive are red- 
ness, swelling, and heat with pain: redness from the congestion of the 
vessels; swelling from the exudation of fluid and corpuscles from the 
congested vessels; heat from the increased amount of blood in the region, 
and pain from the pressure upon and irritation of the terminations of the 
nerves in the region. To these four symptoms may be added a fifth, 
disturbance of function brought about by this departure from the 
normal condition of the region. Under unfavourable conditions where 
the region injured is dense or less vascular, or where the injury is less 
severe one or all of these symptoms may seem wanting; nevertheless 
a minute examination of the tissues will show the same succession of 
changes as in the former case. 
Chapter 2. The Comparative Pathology of Inflammation 
Accepting, then, this working definition, in order to arrive at a due 
comprehension of the succession of changes which we take to constitute 
the inflammatory process, it will be well with Metschnikoff1 to institute 
a series of observations upon the reaction to injury exhibited throughout 
the animal kingdom from the lowest forms upwards to man. By this 
means we shall be enabled to determine what factors in the inflammatory 
process are from their constancy of primary importance; what are com- 
mon and essential, and what are superadded in the higher animals. 
The Response to Injury among the Protozoa. Beginning our study 
with the lowest and simplest forms of life forms so lowly that 
they have been regarded both as animals and as plants we find even 
here phenomena accompanying the reaction to injury which throw light 
upon the inflammatory process as seen in the higher animals. Taking as 
an example the amoeba, we find, in the first place, that the nucleus plays an 
1 The succeeding paragraphs are of necessity very largely an epitome of sundry por- 
tions of M. Metschnikoff’s most pregnant work upon the comparative pathology of inflam- 
mation. By comparing them with the work in question, it will, however, he seen that 
they depart from it in several points; more especially in dwelling upon the extracellular 
activity of the wandering cells, and in bringing more prominently forward the response 
to injury on the part of the fixed cells. INFLAMMA TION 
57 
important part in this reaction. If, as Metschnikoff has shown, one of 
the larger amoebae be cut in two, the region of injury becomes rapidly 
indistinguishable the protoplasm of each moiety closes up, leaving no 
mark or scar; but of the two parts that which retains the nucleus grows 
and proliferates; the other disintegrates in a longer or shorter time. Or 
injury may induce changes in the protoplasm of the entire amoeba: thus, 
Miss Greenwood points out that, without necessarily bringing about 
death, the interrupted current or an aqueous solution of thymol leads to 
a process of exudation or extrusion of clear hyaline spheres, or of spheres 
holding crystals and granules, from the surface of the organism a pro- 
cess resembling that occasionally seen in the cells of an inflammatory 
area in higher animals. Nor is this all; apart from changes in the 
structure of these unicellular animals, differences may be seen in the 
behaviour of amoebae towards foreign bodies. It would seem, according 
to Le Dantec, that amoebae ingest non-irritating foreign substances in- 
differently, provided they be sufficiently small. Around each particle so 
ingested a vacuole is formed, and the fluid in this becomes increasingly 
acid, and at the same time digestive. Krukenberg, lleinke and Miss 
Greenwood have conclusively proved these and similar food vacuoles in 
the amoeba and other Protozoa to contain a pepsine or digestive ferment, 
which, as Le Dantec has shown by very delicate tests, exerts its action 
in an acid medium (the general protoplasm of the cell body being alka- 
line) ; this digestive process leads to the solution of food stuffs, pre- 
paring them to be taken up by the protoplasm of the organism. If the 
foreign substances be incapable of digestion they are sooner or later ex- 
truded. It is by this formation of digestive vacuoles that the amoeba acts 
upon and destroys bacteria, diatoms, and other microbes ingested by it. 
There are, however, microbic forms around which it would seem that no 
proper vacuolation is developed, or if developed, the acid digestive fluid 
is neutralised by substances discharged from the parasites; where this 
is the case, instead of destruction there is continuance of vitality and 
actual multiplication of the invading or parasitic form, leading to the 
eventual death of the amoeba. Metschnikoff has observed this chain of 
events in one of the amoebae which ingests and becomes the host of a 
minute rounded form, the Microsphaera. Phenomena of like nature 
may be observed among the ciliate and flagellate infusoria. While 
these phenomena may primarily be regarded as the method employed 
by the Protozoa for the assimilation of food stuffs, they also are clearly 
the means whereby the Protozoa defend themselves against living 
organisms which have gained entrance into them, and thus form the 
reaction to possible injury; for when in certain cases the means of 
defence are overcome, the parasitic organisms gain the upper hand and 
lead to death. 
There is yet another reaction to injurious influences exhibited by 
the Protozoa into which it is necessary that I should enter at some 
length. This is exhibited by the amoeba, but can be and has been most 
fully investigated in the myxomycetes multicellular forms which SYSTEM OF MEDICINE 
can with equal propriety be classed as animals or plants, although 
usually they are included among the latter. These organisms form 
large plasmodia (masses of protoplasm, that is), in which, under ordi- 
nary conditions, the nuclei are the only indication of the individual 
cells which by their fusion have formed the masses. They are to be 
met with in leaf mould, and on the surface of moist decaying wood over 
which they creep with an amoeboid movement; and inasmuch as they 
may attain great size some species attaining twelve inches or more 
in length they form admirable material for biological study. 
Ten years ago Stahl, investigating one of these myxomycetes (the 
JEthalium septicum, an organism found in tan pits), showed that if placed 
upon a moistened surface close to a drop of infusion of oak bark, the 
plasmodium moved actively towards and into the infusion; if placed 
similarly near to a solution of glucose (05 per cent) it moved with equal 
rapidity away, and so also in the case of solutions of various salts. These 
observations of Stahl were (if we except Engelmann’s observations in 
1881 upon the tendency of sundry bacteria to remove from regions poor 
in oxygen to those where oxygen is present in abundance) the first of a 
series of observations upon the attraction and repulsion of plants and 
portions of plants by chemical substances. To this property,Pfeifer, who 
has made the fullest series of studies upon it, has given the name of 
chemiotaxis, in place of Stahl’s narrower “ trophotropism ”; and one 
speaks of a positive or a negative chemiotaxis according to the attrac- 
tion or repulsion exerted. If, as Metschnikoff has pointed out, the 
advancing edge of one of these plasmodia (of Physarum) be injured by 
cauterisation, the region of injury dies; the protoplasmic currents, 
which had been advancing, reverse themselves abruptly, and within an 
hour the plasmodium has moved away, leaving the debris of the 
destroyed region behind. These experiments are so simple, and the 
results obtained seem so natural, that it may be asked wdiether it be 
worth while to attach a name to this property of living matter. Yet the 
name is in itself an aid to bearing these properties in mind; and, as will 
be pointed out later, the recognition of them is of material help in solving 
certain of the difficulties that present themselves in the study of inflam- 
mation in the higher animals. Among these myxomycetes another fact 
can be made out. Stahl observed that the plasmodium of Puligo, which 
at first moves away from a two per cent solution of common salt, will 
after a time (more especially if it has suffered from lack of water) adapt 
itself to the solution, advancing its pseudopodia or protoplasmic processes 
into it. With other myxomycetes the same adaptation has been observed. 
That is to say, by use or adaptation a negative may be transformed into 
a positive chemiotaxis. To this change I shall have occasion to revert. 
The Response to Injury among the Metazoa. Passing from the 
Protozoa to the Metazoa, we reach immediately (or almost immedi- 
ately) a series of beings in which the division of labour among 
the cells has led to the development of three cell layers —an outer 
ectoderm, an inner endoderm, and an intermediate layer of mesoderm. INFLAMMA TION 
59 
Even in the very lowest forms among the Metazoa it is noticeable 
that of these three layers there is one, the mesoderm, whose cells 
have the especial function of reacting when any irritant or injurious 
stimulation is applied to the organism. Taking what are perhaps the 
simplest forms in which to observe the relationship and properties of 
these layers, Metschnikoff has studied these results of injury in the larval 
forms of astropecten and other echinoderms. At one well-recognisable 
stage these larvae resemble little more than the gastrula stage of the 
embryologist; the endoderm or hypoblast appears as a cul-de-sac —an 
invagination of the ectoderm or epiblast while the mesoderm is repre- 
sented by amoeboid cells, budded off from the endoderm, lying or float- 
ing in the semiliquid substance filling the general body cavity. The 
ectoderm is so delicate that any sharp substance can readily penetrate 
into the body cavity; and, when this happens, it is noticeable that the 
wandering mesodermal cells make their way to the foreign body, attach 
themselves to it, and fuse into plasmodial masses, thus forming a 
wall, as it were, around the invading substance, and cutting it off from 
the general body system. Here, then, in an organism possessing neither 
nervous nor vascular system, the reaction to injury, where that injury 
has not been sufficiently intense to cause destruction of the outer layer 
of cells, is simply and solely confined to the wandering cells of the 
body; there is no effusion of fluid; there is not necessarily phagocytosis 
on the part of these cells; any digestive and destructive action on their 
part any attempt in this way to remove the foreign body must then 
be by excretion, by extracellular action. At the same time, this fusion 
of the cells and formation of a plasmodium around foreign substances of 
greater diameter than the individual mesodermal cells may be looked 
upon as a mechanism whereby the equivalent of intracellular digestion 
is gained. But, as among these low forms cases occur in which, without 
the formation of plasmodia, the cells perform their destructive action 
upon bodies of larger size than themselves we do not lack examples of 
what must be considered as excretory destructive powers on their part. 
That these cells in the echinoderms are also capable of destroying minute 
foreign bodies by intracellular action, that is, by phagocytosis, has been 
demonstrated in the larger transparent larval form known as Bipinnaria 
Asterigera; on introducing bacteria under its ectoderm the mesodermal 
cells are seen to approach, and by their long pseudopodia to adhere to 
and ingest the still living motile bacteria, which are rapidly digested. 
Besides this reaction to injury on the part of the mesodermal cells, 
a further response is exhibited to a remarkable degree among the 
lower Metazoa I refer to the great power of regeneration of lost parts, 
of cell proliferation leading to the reproduction of destroyed regions. 
This power is best seen in the classical example of the Hydra, which 
may be cut into many pieces, each one of which is capable of 
growing, so that in a relatively short time it becomes a fully formed 
individual. It is interesting to note in relation to the frequent ten- 
dency towards hyperplasia and excess growth following upon injury in SYSTEM OF MEDICINE 
the higher animals, that among low forms, such as Hydra and Ceri- 
anthns, the same tendency is yet more strongly marked. Thus, as 
Loeb points out, if an incision be made in the stem of a Hydra, a 
whole new oral pole, provided with tentacles, will branch out from the 
region of cell destruction. In the actinian Cerianthus the process is 
not quite so extensive; yet from the lower lip of the lateral incision a 
set of tentacles develops in all respects similar to those around the 
mouth. 
Ascending to the Worms, we find that the protective agency devolves 
upon mesodermal cells suspended in the perivisceral fluid, and again 
forming the peritoneal endothelium. We arrive, that is to say, at a 
state in which a lymphatic system may be said to be present; for the 
spaces in which the free corpuscles lie are strictly homologous to the 
lymph-containing spaces of the vertebrate organism, and these corpuscles 
may be regarded as lymph corpuscles; the peritoneal endothelium cor- 
responds with the mesodermal peritoneal endothelium of vertebrata. 
Among the annelids the process of reaction to injury may be well 
followed in the earth worm by studying the sequence of changes that 
occur around the gregarines which infest the male genital organs. 
While these parasites are active by their movements they prevent the 
adhesion of the wandering cells; but so soon as they pass into the 
resting stage antecedent to spore formation, the cells form a thick mass 
around them. The parasite on its part forms a thick cyst wall; never- 
theless, it may not nnfrequently be observed that, despite this protection, 
the parasite changes its appearance under the action of the surround- 
ing plasmodium, and in fact is killed. While this is happening no change 
could be detected by Metschnikoff in the neighbouring blood-vessels; 
these appear to remain completely inactive: no exudation is noticeable 
nor any recognisable change in volume. 
While among the Worms a well-developed and closed vascular 
system is not nnfrequently present, in other animal forms, which in 
most respects present a much more complex and advanced develop- 
ment, namely, in the Arthropods and Tunicates, this is not the case. 
In these the blood pours from the tubular heart sooner or later into the 
lacunae of the general body cavity; and whether veins be absent (as 
is most usual), or present (as in the Cephalopods), the blood is sucked 
back from the body cavity into the heart. This incomplete circulation, 
interesting as it is in connection with the development of the vertebrate 
circulation, is interesting also from the fact that its incompleteness 
in these large and wide-spread classes of animals prevents reaction to 
injury from being associated with vascular changes. The blood in these 
animals, circulating through the ramifications of the body cavity, is 
evidently a mesodermal fluid, if it may be so termed. Its corpuscles 
are clearly mesodermal; and without going into full details as to the 
properties of these corpuscles, it may be said that they represent an 
interesting series of stages in the subdivision of labour. For example, 
as Mr. Hardy has shown us in a low form of crustacean like Daphnia (the INFLAMMA TION 
61 
water flea), but one form of cell is present, whereas in the highly- 
developed Astacus (the cray fish), there are three distinct forms of 
leucocytes (no red corpuscles being present), each of which appears 
to have distinct functions. The one form in Daphnia has the property 
of taking up fat globules and food particles from the alimentary 
tract, foreign particles, such as granules of carmine or Indian ink, and 
the spores of parasites (Monospora, Metschnikoff) ; it is granulated, con- 
taining minute spherules which stain with basic aniline dyes (basophile 
granules), and under certain circumstances it may be seen to explode 
with lightning-like rapidity. In the higher Astacus there are in the 
circulating hsemal fluid two varieties of cells: one is extraordinarily 
explosive; when removed from the body cavity it gives off fine blebs 
or vesicles of its substance with such rapidity that, unless the greatest 
care be taken, nothing is seen of the cell save its nucleus; this form is 
phagocytic: the other form is far more stable, and is loaded with large 
spherules which have a great affinity for acid dyes they are eosino- 
philous may be actively extruded, and undergo decomposition; these 
cells never act as phagocytes. The third form, with basophile granules, 
is rarely found in the blood, and then only as the result of special 
stimuli; but it is present in considerable numbers in the peculiar tissue 
which forms a sheath around certain of the arteries Haeckel’s “ Zell- 
gewebe; ” this form is phagocytic, and can be seen to contain globules 
of ingested fat. 
As Metschnikoff demonstrated, in his most remarkable study upon 
a disease of Daphnia caused by the entry of the spores of a yeastlike 
organism (the Monospora) into its body cavity, its one form of leuco- 
cyte can be seen to react swiftly towards the spores; the cells ap- 
proach them, form a plasmodium around and eventually digest and 
destroy them. If, on the other hand, in consequence of their great 
numbers or the relative paucity of the leucocytes, certain of the spores 
be not attacked and develop uninterruptedly into mature torulse, the 
leucocytes show no tendency to approach them —in fact, their neigh- 
bourhood leads to the explosion of the leucocytes and the torulae, 
multiplying, lead to the death of the organism. Often, again, brown 
eschars may be recognised upon the transparent carapace of a Daphnia, 
due to injuries by other individuals; beneath these scars are to be found 
masses of leucocytes which remain in the region of injury until the cells 
of the tissue have proliferated, and there is complete union and repair. 
In addition, then, to the immediate reparative and protective re- 
action of the leucocytes, there is exhibited among the higher invertebrata 
a later reaction in the shape of proliferation of the fixed cells. This 
proliferation, while not so extensive as among the lower invertebrates, 
can nevertheless be very great; and cells of all forms, whether of hypo-, 
meso- or epiblastic origin, and tissues so highly developed as the muscular 
and nervous, may participate in it. In illustration of the ample power 
of tissue reproduction after injury possessed by these animals, I need but 
mention the trite examples of the reproduction of the hinder segments 62 
SYSTEM OF MEDICINE 
of divided worms, and in crustaceans the restoration of injured and cast 
off claws and appendages. 
Many more instances might be given to show that the reaction to 
injury remains essentially a reaction on the part of the wandering and 
fixed mesoblastic cells of the organism, followed in sundry cases by 
proliferation of the fixed epi-, meso- and hypoblastic cells, and by repair 
where these have been destroyed. Although these arthropods, molluscs 
and tunicates have a vascular system, yet, inasmuch as this is open, its 
changes, if they occur, could scarcely modify the inflammatory process. 
The Response to Injury among the Vertebrata. If now we pass to 
the vertebrates, the picture presented is far more complex: not only do 
these present a highly-developed nervous system, but, moreover, the 
blood is enclosed in a complete vascular system. We shall now consider 
at length the results of an injury of an organ in one of these higher 
animals. 
Chapters. The Main Forms op the Process of Acute Inflam- 
mation in the Higher Animals 
The Experimental Production of Inflammation in Non-Vascular Areas. 
Let us begin with the succession of changes that occurs in the sim- 
plest case, namely, in a non-vascular area, in one of the lowest vertebrate 
forms for instance, in the embryonic axolotl ten to fifteen days old; 
let us curarise it, and apply a minute crystal of silver nitrate to the 
side of its flattened transparent tail fin, washing away the remains of 
the crystal with salt solution; or again, we may pass into the tail a 
small needle filled with finely-powdered carmine. By either procedure 
a certain number of cells is destroyed. The neighbourhood of the 
injury now becomes swollen (it may be by imbibition of water through 
the wound), and the surrounding cells tumefied, vacuolated and less 
refractile. This is the first stage—that of injury and modification of the 
surrounding tissue. In a little time a few wandering cells (leucocytes) 
approach the injured region; by the next day these are present in 
fair numbers, and can be seen to have taken up the particles of carmine 
or debris of the destroyed tissue. This is the second stage that of 
immigration of leucocytes. There are no vessels in the transparent 
fin of these young axolotls, no dilation of those nearest to the fin, 
and no diapedesis. All the leucocytes that pass to the part are pre- 
existing wandering cells of the connective tissue,—a fact of some little 
importance in connection with the origin of certain of the pus cells in the 
suppurative process of higher animals. The third stage is that of repair, 
of proliferation of the injured epithelium, return of the fixed cells of 
the tissue to their previous state, and emigration of the wandering cells. 
A very similar progress of events occurs if the experiment be repeated 
upon the tail fin of the young newt. The same rapid alteration in the 
large branched connective tissue cells (which become vacuolated as their INFLAMMA TION 
63 
long processes are drawn in and shortened), and the same immigration 
of motile cells from the surrounding connective tissue are to be seen; 
but here we now find the earliest evidence of vascular participation, for, 
according to Metschnikoff, complete arrest of the circulation may occur 
in the nearest vascular loop. By the next day the parts have returned 
to the normal condition. 
If from these cases we pass to mild inflammatory disturbances 
affecting the non-vascular regions of animals far higher in the scale, we 
again discover a like process of events. For this purpose the cornea 
affords an excellent opportunity; in health it is absolutely non-vascular; 
it is perfectly transparent, and is so thin that it can readily be examined 
microscopically. 
The cornea of mammalia, and indeed of vertebrates in general, is 
formed of fibres which run in layers parallel to the surface. These 
fibres, while roughly arranged side by side and parallel to one another 
in any given layer, are placed at an angle to the fibres of the layers 
above and below. Although free from blood-vessels the cornea is 
far from being devoid of channels along which lymph freely passes. 
Between the several layers there exist spaces in which lie the flattened 
connective tissue cells of the organ; and, by means of numerous fine 
channels, these spaces around the cells are connected with similar 
spaces lying anteriorly, posteriorly and laterally. Through this rich 
anastomosis of channels there is a free flow of lymph. These channels 
are really continuations of the body cavity of the animal; they repre- 
sent, and in fact play the same part as the single body cavity of such a 
simple form as the larva of Astropecten, while the cells lying in the 
spaces are mesoblastic cells which have become fixed. 
Few studies are better calculated to impress the investigator with a 
sense of the depth of the well at the bottom of which truth lies, than a 
research into the abundant literature dealing with observations upon the 
stages of the inflammatory process as it occurs in the cornea, and with 
the deductions therefrom. One after another the adherents to succes- 
sive forms of inflammatory belief have found in experiments upon this 
simple tissue ample support for their particular creeds. 
Selecting from among the many observations those which have stood 
the test of time, I will begin with the simplest, and pass on to those 
dealing with an increasing intensity of the inflammatory process. 
If, as Senftleben first pointed out, the centre of the cornea of a 
rabbit be washed with a strong solution of zinc chloride, then, in favour- 
able cases, although the epithelial covering be gravely injured, there may 
be no actual rupture of the outer layers of the tissue. Such a cornea 
removed twenty-four hours later may show no sign of migration of 
leucocytes—no sign, again, of congestion of the vessels at the peri- 
phery. The only indications of injury and reaction may be the destruc- 
tion of the corneal corpuscles immediately beneath the cauterised area, 
and the appearance of a zone surrounding this in which the corneal 
corpuscles appear enlarged, distinct and tumefied. The process may 64 
SYSTEM OF MEDICINE 
continue and advance insensibly to repair without the intervention of 
leucocytes; the hypertrophying cells of the “ granular ” zone eventually 
undergoing karyokinesis, and thus by multiplication replacing the cor- 
puscles destroyed. 
Here, then, necrosis and new growth of the fixed cells of the tissue 
are the only recognisable factors in the process of repair of injury. It 
must be confessed that the conditions permitting this simplest form of 
reaction are of rare occurrence; it is worthy of attention that they can 
exist. 
By a slight modification of the preceding conditions another factor 
may be brought into play. If, after cauterisation in the manner above 
described, a break be made into the cauterised surface; or if again, 
without cauterisation, a little of the corneal tissue be removed, then in 
a few hours a small whitish opacity is to be noticed within the corneal 
tissue in the immediate neighbourhood of the break in the continuity, and 
upon examination this opacity is found to be due to a massing of small 
round cells. As there is at this moment no sign of proliferation of the 
connective tissue cells of the cornea, these newly-collected cells can only 
be leucocytes; and further examination of their properties proves them 
to be such; there is, however, no evidence of dilation of the peripheral 
vessels, no indication of diapedesis through their walls. The leucocytes, 
therefore, can only have entered into the wound from the cornea itself 
and from the conjunctiva and the lachrymal fluid bathing it. In this 
experiment the inflammatory process is represented by destruction of 
tissue and immigration of leucocytes, followed by repair; neither the 
vascular nor the nervous system play any part in it. We are forced to 
the conclusion that the leucocytes have massed themselves in the 
injured area purely on their own initiative; and that there must be an 
attraction, a chemiotaxis or chemiotropism, leading them actively to 
approach the region of cell destruction. 
The observations made upon these two simple cases help us materi- 
ally to understand the series of events which occur in more intense 
inflammation of the cornea, such as that produced by injuring the surface 
and causing the entrance into the injured region of a small quantity 
of a pure culture of the Pyococcus aureus. This may be accomplished 
by injecting the culture into the centre of the healthy cornea by means 
of the needle of a Pravaz syringe (Jacobs). The micrococci so intro- 
duced grow rapidly, the growth so extending along the lymph spaces 
that a branched mass of the microbes is produced, having the spot of 
inoculation as centre. Around the growth as it extends may be seen 
a sharply-marked area in which the corneal corpuscles show evidences 
of degeneration; the nuclei stain faintly, and the corpuscles, speaking 
generally, have a shrunken appearance. Here, again, the first effect of 
a microbic, as of a simple chemical injury, is to bring about degeneration 
of the fixed cells of the tissue. Within eighteen hours the zone of pro- 
liferating cocci and cell degeneration is well marked; and now the 
second stage begins to be clearly manifest, namely, the determination INFLAMMA TION 
65 
of leucocytes to the seat of injury. Within twenty-four hours there 
is a dense packing of these corpuscles around the central degenerated 
area, and great numbers of leucocytes may be seen converging along the 
lymph spaces from the periphery of the cornea. This is the second stage 
of the process, the first stage of reaction to the injury inflicted by the 
invading micro-organisms. If, as by Cohnheim1 in his original experi- 
ments upon the injury to the cornea, more careful examination be made 
into the stages of the determination of leucocytes, it can be seen that this 
determination is closely related to changes set up in the vessels at the 
periphery of the cornea; they become more prominent, the region has a 
congested appearance, the smaller as well as the larger vessels are 
dilated, and there is abundant evidence that the leucocytes are passing 
out from the contained blood into the surrounding lymph spaces. In- 
deed the accumulation of leucocytes shows itself first at the periphery of 
the cornea near the vessels, and gradually approaches the region of 
injury. Into the mechanism of this diapedesis, and into a fuller descrip- 
tion of the changes that take place in the blood-current in these distended 
vessels, I shall enter later when discussing the changes in highly vascular 
regions. Suffice it to say here that no distinction can be made out between 
the behaviour of the leucocytes in the previous experiment, when they 
entered the wounded area from the external surface, and in this where 
the majority find their entrance from the blood; as in the previous case 
the part played was evidently active, so must it be here also. We cannot 
arrive at any other conclusion than that some attractive force leads to 
their determination towards the inflammatory focus. As we can easily 
show, by repeating the experiment, many of these leucocytes take up and 
contain numerous cocci, while other cocci remain free in the tissue 
spaces. Many of the leucocytes degenerate and present a broken down 
appearance; and, as at the same time an increasing area of the corneal 
tissue becomes disintegrated, an ulcer appears. According to the viru- 
lence of the culture and the reaction on the part of the organism, the 
process may now extend, a larger and larger portion of the corneal 
tissue becoming affected; or, on the other hand, there may be an arrest 
of the progress, the massing of the leucocytes preventing, as a barrier, 
the further extension of the micrococci into the lymph spaces;2 while 
at the same time there is an advance of newly-formed capillary vessels 
into the previously non-vascular tissue. It is to be noticed that the 
blood-vessels at the periphery of the cornea are prominent and dilated, 
and from them fine new vessels with very delicate walls pass towards 
the injured region. At the same time many of the corneal corpuscles, 
outside the area of destruction, can by appropriate staining be seen 
undergoing mitosis and proliferating. Thus the active repair of the 
tissue is initiated. 
1 There can be no question that Cohnheim in his experiments induced not a simple 
keratitis but one which in the absence of aseptic precautions rapidly became septic and 
suppurative. 
2 Into the details of this action I shall enter more fully later. 
von. I y 66 
SYSTEM OF MEDICINE 
The Experimental Production of Inflammation in Vascular Areas. 
From this study of inflammation, as it occurs in a region devoid of 
blood-vessels, let us now pass on to the more complicated process of 
inflammation in vascular areas; and, as in the previous case we considered 
an ascending or advancing series of reactive changes, so here let us begin 
with the slightest injury associated with the mildest reaction, and pass 
onwards to states in which the inflammatory manifestations are more 
and more pronounced. 
If an incision be made with a perfectly aseptic instrument into the 
skin, also rendered aseptic, and be so made as to divide the dermis 
and tissues immediately below, without at the same time injuring any 
large vessel, it is the common experience of modern surgeons that 
repair takes place with the minimal amount of change recognisable as 
inflammatory. Repair takes place indeed so rapidly that, if the 
divided structures have come or have been brought into immediate 
contact, there may be firm adhesion at the end of twenty-four hours. 
This is primary union, or union by first intention, which, rare in the 
old days, commonly occurs in this era of aseptic surgery. The full 
sequence of events in these cases cannot, it is true, be well determined 
by continuous microscopic examination; but if the rabbit or dog be 
employed, and tissues, wounded in the manner described, be removed 
and examined at successive short intervals, we see that the changes 
which occur are mainly, nay almost entirely, related to the pre-existing 
cells of the part. The section divides a certain number of capillaries; 
but in the very act of division the divided walls are apparently brought 
together; and, partly by this means, partly by contraction, the lumina of 
these minute vessels become occluded, and the haemorrhage into the 
wound is altogether inconsiderable. Within an hour after the operation 
it is evident to the naked eye of a careful examiner that the immediate 
neighbourhood of the wound is slightly reddened and tumefied, but 
only very slightly ; and, associated with this, there is a feeble exudation 
between the apposed surfaces. But the exudation is not great, and 
even within this first hour after the infliction of the wound there may be 
development of fibrin and coagulation of the exudate, leading to the 
formation of a provisional cementing together of the opposed surfaces. 
In this exudation, and in the tissues in the immediate neighbourhood, 
the leucocytes that have undergone diapedesis may be few and far- 
between, and may scarcely attract attention. The reaction, then, on the 
part of the vessels and of the leucocytes is of the slightest. Study of 
sections shows that the main role is played by the pre-existing cells of 
the part; of these a certain number (not so many as might d priori be 
expected) are destroyed immediately, and show all the signs of disinte- 
gration ; a number relatively large have been injured only, their nuclei 
remaining intact, though their processes or some portions of the cell 
bodies have been cut through. It is difficult to determine these 
injuries in the small cells of the cutaneous tissues; they are better seen 
in the peritoneum when slight inflammatory changes have there been INFLAMMA TION 
67 
induced. This, however, can be made ont that the cells in the immedi- 
ate neighbourhood of the wound became enlarged, and, without showing 
signs of division, prolong themselves (that is to say, send out prolonga- 
tions) into the region of the provisional fibrinous cicatrix. In this way, 
before the end of the second day, there may be a more or less complete 
replacement of the primary unorganised cementing substance by organ- 
ised growing tissue, formed, in the first place, by the interlacing of 
processes from the neighbouring cells; in the second, and later, by a 
multiplication of these cells, together with a development of new 
capillaries, few in number, which branch off from the slightly-congested 
vessels in the neighbourhood. Thus in this case the process of repair 
is characteristically associated with hypertrophy and the new growth 
of the fixed cells of the tissue; while vascular changes, exudation and 
leucocytosis, are relatively little marked. I have, however, never come 
across a case in which they have been entirely absent, save when the 
section has been truly extra-vascular that is to say, when it has not 
penetrated into the vascular region of the skin, and has affected only 
the epidermis and outermost layers of the dermis. In such cases the 
response to injury may show itself purely as a proliferation of the 
epithelial cells. 
As I have said, observations of the above nature labour under the 
disadvantage that they must of necessity be discontinuous. I bring 
them in at this point, inasmuch as they represent the mildest condition 
of the inflammatory reaction. I have not personally observed this 
series of changes in tissues which permit of continued study under 
aseptic conditions; neither am I acquainted with any observations 
wholly fulfilling these conditions made, that is to say, upon trans- 
parent vascular tissues subjected to the mildest aseptic injury and 
examined continuously under the microscope. 
The response to injury in the cases just mentioned was of the 
slightest. Let me now pass on to cases in which it becomes more pro- 
nounced; and in order to continue the comparative study of inflam- 
mation I would first describe the series of events in a highly vascular 
and transparent region in a low vertebrate animal, namely, in the 
tadpole’s tail. If this be injured, either by the application of a caustic 
or by the introduction of a foreign inert body into its substance, a 
definite advance upon what was recognisable in the case of the axolotl, 
for example, is to be made out. Here the tail is very vascular, the 
wandering cells of the connective tissue are very few in number, while 
the blood is fairly rich in leucocytes which are small relatively to the 
size of the vessels. The results of injury are a congestion of the 
vessels, noticeable within fifteen minutes, and a well-marked determi- 
nation of leucocytes to the injured region. These cells, in the main, 
pass out from the vessels; the few leucocytes pre-existing in the tissue 
appear to play a very small part. Compared with the axolotl experiment 
this observation is of considerable interest. Instead of a slight reaction 
slowly developing there is a rapid reaction; instead of a slight accurnula- 68 
SYSTEM OF MEDICINE 
tion of leucocytes there is a most pronounced accumulation. If there be 
any meaning in the determination of leucocytes to the region of injury, 
then evidently the active participation of the vessels of that region in 
the reactive process is fraught with benefit —it is a further important 
factor developed with the development and advance of the organism. 
The fuller details of this vascular interference in the inflammatory 
process have been followed by many observers, among whom first and 
foremost was Cohnheim; and to this end the frog has supplied the most 
convenient means in regions at once vascular and fairly transparent, 
such as the web of the hind feet, the tongue, and the mesentery. Other 
observers passing higher in the scale of vertebrates have employed the 
mesentery of the cat, dog, and other mammalia. Suffice it to say that, 
with slight modifications due to local conditions in the tissue examined 
rather than to the animal selected, the process has been found to 
present the same features throughout the whole of the adult vertebrata, 
from the reptilia upwards. For general examination, perhaps, the best 
and simplest method of observing the succession of changes that follow 
injury of a vascular area is to be found in what I believe to be Coats’ 
modification of Cohnheim’s original experiment upon the frog’s web 
(Coats’ Pathology, 1889, p. 119). In order to reproduce as nearly as 
possible the conditions of an ordinary wound, instead of employing a 
caustic or chemical irritant, a small portion of the cutaneous surface is 
nipped off the section being just deep enough to pass through the 
cutaneous layers without causing haemorrhage. For the experiment to 
proceed satisfactorily, it is necessary that the frog be curarised after 
having been pithed. The web of a small frog is so thin that the 
changes occurring in and around the vessels of the part can readily be 
followed even with a high power of the microscope. 
The first change noticeable in the immediate neighbourhood of the in- 
jured membrane is a dilation of the vessels, first of the arteries and then of 
the veins; and in this first phase there is a very evident acceleration of 
the blood flow. At this early period the capillaries show little evidence 
of dilation, but in the course of an hour expansion is readily distinguish- 
able, and sundry capillary channels, previously invisible, become occupied 
by blood and show themselves. This first stage lasts for an hour, or in 
some cases perhaps two, and is followed by a phase of slowing of the 
blood current. While previously a well-marked axial stream of cor- 
puscles had been evident, with a peripheral zone of plasma devoid of 
corpuscles, the former now broadens out, the latter becomes less and 
less, and as it narrows an increasing number of the clearer rounded 
haemal leucocytes are to be seen in it travelling at a slower rate than 
the more axial stream, and every now and then stopping beside the 
walls of the vessels, and after a short stoppage passing on again. The 
leucocytes conduct themselves as if they have become “ sticky.”1 
As the current becomes yet slower all distinction between axial and 
1 Even so low down in the scale as Daphnia this same peculiarity is noticeable; there in 
health, as Hardy has pointed out, the leueoeytes move freely; but, if the slightest injury he INFLAMMA TION 
69 
peripheral streams is lost; the corpuscles, closely packed together, fill the 
whole lumen; the leucocytes in increasing number approach the vessel 
walls; they adhere more firmly, and so long as a current is recognisable 
the action of the stream leads them to assume a pear-shaped appearance, 
the rounded ends pointing in the direction of the current. 
As the stream slows gradually the corpuscles may move at last in a 
series of jerks synchronous with the heart beats; or frequently in the 
veins and capillaries the mass of blood may be seen moving slowly first 
in one direction, then in the other. Frequently one or other of these 
stages is followed by complete stagnation or stasis of the blood in the 
vessels of the injured area I say frequently, for at other times little 
or no absolute arrest is seen in the vessels. Accompanying this stage, 
although observers employing other and chemical methods of inflicting 
injury have in general omitted to call attention to the fact, there is 
already a considerable oozing or exudation of clear fluid from the wound; 
there is, that is to say, an outpouring of lymph, and that apparently from 
the distended vessels. Now, with the slowing of the stream the 
leucocytes, accumulated next to the walls of the small veins and within 
the capillaries, pass from the interior to the exterior of these vessels; 
and, if the process be studied carefully with a higher power, it can 
be seen that this mode of passage is of an active, or apparently active 
nature.1 A series of leucocytes can be distinguished some of which are 
rounded or flattened in immediate contact with the wall of the vein; 
others possess a prolongation passing into the wall; in others, again (or 
in the former if they be watched in the fresh specimen), the prolongation 
enlarges on the outer side of the small vessel while the portion of the 
leucocyte within the vessel becomes smaller. The final phase of this act 
of diapedesis is that the whole leucocyte passes through, and is found in 
the lymph spaces around the vessel wall. This process of diapedesis 
may be so general that in the course of five or six hours all the small 
veins of the region show a crowd of leucocytes situated along their outer 
surface. With these a greater or less number of red corpuscles may 
also make their escape. 
Although the capillaries, from the very smallness of their diameters, 
do not show the so-called “ margination ” of leucocytes, nevertheless this 
same process of diapedesis may occur at various points along their course, 
so that outside the capillaries also a fair number of the same small highly- 
refractile cells endowed with amoeboid movements can be observed. 
In this modification of Cohnheim’s experiment a further stage is to be 
recognised. While at first the fluid exuded was clear and relatively free 
from cells and cell debris, now, as the inflammatory process continues, an 
increasing number of leucocytes is contained in the exudation. The 
inflicted upon the carapace, the leucocytes, previously unadhesive, soon show the tendency 
to adhere to the walls of the body cavity beneath the region of injury and elsewhere. 
1 The process can he fully made out if at this stage the wounded region be removed, 
fixed immediately in weak osmic acid, and prepared for examination by the higher 
powers of the microscope. SYSTEM OF MEDICINE 
leucocytes do not remain in the immediate neighbourhood of the vessels, 
but many of them pass on to the injured surface; still it would seem by 
active amoeboid movement. Thus at the end of six hours this surface 
may be covered by a serum or fluid in which are great numbers of these 
leucocytes. Here then we have the first step towards the formation of 
a scab or provisional protective covering to the wound. 
Further observations cannot well be carried out in the pithed and 
curarised frog; but if an unpithed, non-curarised animal be taken, and 
the observations upon the earlier stage be neglected, it can be made out 
that if irritant matter do not find entry into the wound the process may 
be arrested at this point; the leucocytes upon the surface may break 
down, and with their breaking down and the formation of fibrin a soft 
scab be formed: the stasis of the blood in the distended vessels may be 
followed by a re-establishment of the current and slow return of the 
vessels to their former calibre, while beneath the thin, soft scab the 
epithelial cells rapidly proliferate. Within twenty-four hours there may 
be abundant evidence of this new growth of the epithelium tending 
to encroach upon and cover the wound. At the same time the region 
becomes less and less populated with leucocytes, so that not to enter 
fully at this point into the reparative process within sixty hours the 
region may show little sign of the injury and consequent inflammation. 
On the other hand, if irritants of a microbic nature enter the wound 
the process may extend, as in inflammation of the cornea. More especially 
if the water in which the frog is kept become foul, there is a tendency 
in the inflammatory processes to spread; and in the cells of the central- 
area, both fixed and migrated, to break down, leading to the formation of 
a spreading ulcer. The steps of this sequence of affairs it is difficult to 
follow by continuous microscopic examination, partly on account of the 
increased opacity of the region, partly because the process extends over 
days rather than hours. Here, therefore, I merely mention this possible 
extension of the change with its main naked-eye appearances. 
It is not possible by continuous observation to make out the steps of 
this more extensive inflammation characterised by excessive emigration 
of leucocytes and destruction of these together with the fixed cells of the 
tissue the pyogenetic inflammation. Several observers, however, have 
followed its successive stages by means of examination of affected tissues 
at successive intervals after the infliction of injury. 
The Experimental Production of Suppurative Inflammation. While, 
as shown by Councilman, Grawitz and de Barry, Straus, Leber and 
others, a suppurative inflammation may under certain conditions be 
brought about experimentally by the action of chemical irritants, such 
as mercury and turpentine; yet under ordinary pathogenic conditions 
suppuration is induced by the growth of micro-organisms within the 
tissues. Hence it is better to study the conditions as induced by the 
inoculation of pus-producing microbes into one or other tissue. A very 
full series of observations upon the development of abscesses through the 
agency of the Staphylococcus pyogenes aureus has been made by Hohn- INFLAMMA TION 
feldt. He employed rabbits, and inoculated small quantities of pure 
cultures of the microbe subcutaneously. 
Pour hours after inoculation the vessels of the region were found 
densely filled with corpuscles, and in them a commencing margination of 
the white corpuscles was discernible. Leucocytes were present within 
the tissue in numbers greater than normal; although, compared with later 
stages, they were infrequent. They were of two kinds the mono- 
nuclear in the majority, the polynuclear (or more truly the form with 
polymerous nucleus) in lesser numbers; both forms were congregated 
mainly around the line of entrance of the injecting needle. Many of 
the connective tissue cells were so swollen as to be rounded rather than 
flattened. The injected cocci, lying in the lymph spaces, were scattered 
through the tissue; in part free, in part already ingested by cells, not 
only by the leucocytes, but also by connective tissue cells: the number 
within leucocytes was not inconsiderable. 
Preparations made at the end of ten hours showed the same conditions, 
but more distinctly. There was ample evidence of migration of the 
leucocytes, margination in the congested vessels, various stages of passage 
through the vascular walls, and large collections of the cells in the peri- 
vascular lymph spaces; from these they spread into the spaces between 
the bundles of connective tissue fibrils. The cocci lay in the lymph 
spaces and were increased in number, and the massing of leucocytes cor- 
responded in position to the accumulation of microbes. In these regions 
the leucocytes were mainly polymerous or multinuclear, but in the boun- 
dary zone away from the cocci the uninuclear form predominated. 
At the end of twenty hours there was further accentuation of these 
conditions. As yet an abscess proper had not formed, but enormous 
numbers of leucocytes were present, and also of micrococci; the fibrillse 
of connective tissue were widely separated by the collections of leuco- 
cytes, and these cells clustered round and hid the connective tissue cells. 
With the completion of forty-eight hours a well-defined abscess had 
formed, separated sharply from the surrounding healthy tissue. The 
centre of the abscess was seen to consist of densely-packed leucocytes 
mingled with large growths of cocci. These leucocytes were almost 
entirely “ multinuclear; ” and in this central area the nuclei of some 
showed fragmentation. Neither leucocytes nor connective tissue cells 
showed the slightest indication of mitosis. In the central area all traces 
of the previous capillaries had disappeared; in the peripheral zone they 
were easily recognisable, being fully injected and showing a marginal 
disposition of their leucocytes, many of which could be seen (in osmic 
acid preparations) fixed in the process of diapedesis. 
The majority of the cocci lay in these leucocytes. Even where the 
colonies of the microbes were thickest there the majority were intra- 
cellular. Passing towards the periphery the number of cocci became 
smaller and smaller. At the periphery they could be seen not only to 
be intracellular, but also free in the lymph spaces; and Hohnfeldt, with 
other observers, saw them definitely grouped within the endothelial cells 72 
SYSTEM OF MEDICINE 
of the peripheral vessels. Thus it may be noted that at this stage the 
proliferating microbes extended into the healthy tissues outside the 
abscess. 
In the centre of the abscess the original tissue had wholly disappeared; 
nearer the periphery light streaks and bundles of the disintegrating 
fibrillse could be recognised between the leucocytes. 
Not till about the tenth day did new growth of tissue begin to show 
itself. During the preceding six days there had been more breaking 
down of the polynuclear leucocytes, characterised by fragmentation of the 
nuclei and by fatty degeneration of the cell substance. But by the tenth 
day the periphery had begun to assume the appearance of granulation 
tissue; it contained numerous capillaries and new-formed connective tis- 
sue with characteristic epithelioid cells or fibroblasts possessing large oval 
pale staining nuclei. In these cells, as in the connective tissue cells of 
the surrounding healthy tissue, could the numerous steps of indirect cell 
division be made out. In this granulation tissue cocci were absent and 
leucocytes were infrequent. In the soft, cheesy central area masses of 
cocci were still present. Whether these were living or dead Hohnfeldt 
did not determine; he inferred (what has since been proved by several 
observers to be an unsafe inference) that inasmuch as they stained well 
with aniline dyes they were alive. 
Thus, to sum up Hohnfeldt’s observations, the processes occurring in 
a suppurative inflammation that ends in healing are the following; 
1. Congestion of the region of invasion, with margination of the 
leucocytes. 
2. Collection, in the region, of uninuclear leucocytes; then diapedesis 
of leucocytes with polymerous nuclei: multiplication of the cocci. 
3. Ingestion of large numbers of the microbes by the polymerous 
leucocytes and other cells, including the endothelial cells of the vessel 
walls. 
4. Increasing immigration of leucocytes until the tissue becomes 
densely packed. This is accompanied by a yet greater proliferation of 
the microbes, which extend (i.e. are carried by lymph streams or by cells) 
into the region outside the developing abscess. 
5. Destruction of the tissue of the affected part. 
6. Degeneration of the leucocytes within the sharply-defined abscess. 
7. Eventual proliferation of the connective tissue at the periphery of 
the abscess; formation of fibroblasts in the highly vascular surrounding 
zone; cicatrisation and encapsulation of the debris of the leucocytes 
and micrococci. 
There are not a few points in connection with these observations of 
Hohnfeldt that deserve discussion; very possibly he has misinterpreted 
certain of the appearances seen by him. On the whole, however, he 
draws a full and accurate picture of the successive stages of suppurative 
inflammation, and I may defer discussion to a later review of the action 
of the leucocytes and of the formation of fibrous tissue respectively. 
However, before leaving this general description of the series of INFLAMMA TION 
73 
anatomical changes induced by injury, there is another phase of the 
inflammatory process set up by pathogenic micro-organisms which must 
not be passed over I refer to those cases in which, instead of ending 
in repair, there is extension and generalised disease. The stages pre- 
ceding extension vary with the natmp of the microbe; thus, in some 
cases, the reaction to the invasion of the microbe is mainly leucocytic 
(as with inoculations of the micrococci of suppuration), in others it is 
mainly exudative or serous, the congestion of the vessels being followed 
by abundant exudation of serum into the tissues. This is the case in 
inoculation of animals such as rabbits, guinea-pigs and fowls with 
cultures of micro-organisms which are peculiarly virulent in their be- 
haviour towards these animals. Such a serous or exudative inflamma- 
tion is, for instance, well seen if the vibrio Metschnikovi be inoculated 
into the pectoral muscles of a fowl. Within twelve hours, it may be, 
the seat of inoculation becomes greatly swollen, and on section is found 
reddened and congested; while from it drains an abundance of relatively 
clear, faintly-reddish serum containing but a few leucocytes. 
In such a case as this the micro-organisms appear to pass with ease 
from the centre of infection into the surrounding tissues, and thence 
into the lymphatics and general circulation, whence they may be 
obtained within twenty-four hours. Where there has been a well- 
marked abscess formation in the region of invasion there, as already 
indicated, it is true that the microbes may be found outside the abscess 
at a fairly early period; but, in the main, proliferation is limited to the 
abscess, and the blood remains free and sterile. Under certain condi- 
tions of great virulence of the pyogenic microbes it is found that as the 
abscess extends it becomes ill-defined there is no sharp demarcation 
between the collected leucocytes and the surrounding tissue; the 
columns of leucocytes spread indefinitely from the centre, and numerous 
micrococci are intermingled with them. Where this is the case there 
is a marked tendency for the microbes to find their way into the general 
circulation from this irregular peripheral extension along the lymphatic 
spaces, and to set up a condition of septicaemia as in the more serous 
inflammation described above. 
Septicaemia, or the passage of micro-organisms into the blood, with 
all the results of such a passage the condition which sundry French 
observers have described as inflammation of the blood —is dealt with 
in another article. In septicaemia we pass beyond the local response to 
injury, we deal with a state of general systemic disturbance. Never- 
theless certain phases of the septicsemic condition throw light upon the 
inflammatory process. 
In the first place, it is of interest to note that when the infective 
micro-organisms and their products are within the vessels they fail to 
induce the cardinal symptoms of inflammation. They do not lead to 
exudation of fluid from the blood or to wide-spread diapedesis of leuco- 
cytes. The stimulus, whatever it be, which leads to these phenomena at 
the point of invasion is no longer called into activity when the noxa is 74 
SYSTEM OF MEDICINE 
within the circulatory apparatus. This is the reverse of what might be 
expected if the inflammatory process were primarily due to a modification 
of the endothelium of the vessel walls by the irritant, a modification pas- 
sively permitting the exudation and passage outwards of the leucocytes. 
The statement that infective micro-organisms and their products 
circulating within the blood fail to induce inflammatory changes, would 
seem to need modification when the development of metastatic abscesses 
is taken into account. But a study of the mode of production of these 
abscesses shows that the statement still holds. Such abscesses originate 
round emboli of pyogenic micro-organisms in the capillaries. Sundry 
cocci are arrested in the capillary, proliferate and fill the vessel. It is 
only when a minute vessel is thus occluded that the abscess process 
begins, that is to say, when by this occlusion the vessel has become 
extravascular ; and while it is true that, primarily, the arrest of patho- 
genic microbes within the capillaries is often associated with a small 
accumulation of intravascular leucocytes and with degenerative changes 
in the vascular endothelium, the metastatic abscess, as such, forms not 
by accumulation of leucocytes in the occluded vessel, but around it; 
the leucocytes emigrating from surrounding capillaries. 
Inflammatory Fever. ln the second place, through this study of 
advancing inflammation it is of interest to trace the very close relation- 
ship that exists between inflammation and fever. Besides the local 
changes here described, local injury is accompanied by systemic dis- 
turbances. These may be slight or grave. 
Take, for instance, progressive abscess formation, or follow the 
development of a malignant carbuncle in man. At first the reaction 
is purely local, but very soon, long before any of the micro-organisms 
are capable of detection in the blood, there is exaltation of temperature 
and a slight febrile state, the fever becoming more and more evident as 
the local process becomes more and more extensive, until with the 
detection of the microbe in the blood the most severe fever, with con- 
stitutional disturbance, sets in. Local inflammation, then, without any 
other possible explanation than either the nervous irritation to which 
it may give rise, or the passage into the general circulation of the 
soluble products of bacterial growth and tissue destruction, or both, 
may lead to the development of the febrile state. How large a share is 
played by these two possible factors it is difficult to say. That 
bacterial products injected into the circulation lead to the rapid pro- 
duction of the febrile state we have ample evidence ; but whether these 
act directly by inducing increased cellular activity, or indirectly by 
stimulating the cerebral centres, we cannot absolutely say. As yet we 
have little accurate knowledge of the parts played by the nervous 
system in the development of the febrile state. This, however, may 
safely be declared, that the more we study the continued fevers the more 
do we discover that these commence by a local inflammatory disturbance. 
The continued fevers are the continuance, or rather the extension, of a 
primarily localised inflammatory lesion. [Vide art. on “Fever.”] INFLAMMA TION 
75 
Summary of the Facts thus far brought forward. 
The main facts gathered thus far concerning the inflammatory pro- 
cess, and the conclusions to be drawn therefrom, may now be placed in 
order before I discuss in detail the various factors in the process. They 
are 
1. Injury, when it is not so widespread and severe as to lead to the 
death of the individual, is followed by a reaction on the part of the 
organism. 
2. In unicellular organisms the continued vitality of the individual 
after injury, and in multicellular organisms the vitality of the indi- 
vidual cells, are dependent primarily upon the persistence of the 
nucleus; if this be destroyed or removed the rest of the cell is incapa- 
ble of complete restitution and continued growth. 
3. In unicellular organisms the reactive process is twofold, and con- 
sists of (a) destruction or removal of the irritant; destruction being 
brought about by a process of intracellular digestion, removal by extru- 
sion of the irritant; (6) new growth of the organism. 
4. This response to injury on the part of unicellular organisms is 
essentially reparative. 
5. In multicellular organisms, with division of labour among the 
constituent cells of the individual, there is a separation of functions; 
the twofold reaction to local injury is yet more clearly marked; but 
(a) The destruction or removal of the irritant is in the main accom- 
plished by the wandering cells of mesoblastic origin. 
(b) The new growth to replace the tissue destroyed by the irritant 
proceeds in the main from the fixed cells of the tissue. 
6. Ascending the scale of multicellular organisms, a division of 
labour and differentiation of function is discoverable among the wander- 
ing mesoblastic cells. Whereas in the lower forms of the Metazoa one 
type of leucocyte alone is present, in the higher forms two or more 
varieties can be distinguished which possess different properties and 
act differently towards irritants introduced into the system. 
7. According to the nature of the irritant causing the injury, the 
leucocytes are actively attracted in greater or less numbers to the 
region of injury, surround the irritant, and remove or destroy it by 
means very similar to those employed by unicellular organisms. Where 
the irritant is present in the form of discrete particles, there some at 
least of the leucocytes may incorporate the particles, and remove them 
or destroy them by a process of digestion. Others of the leucocytes in 
the higher Metazoa never act thus as phagocytes; nevertheless they are 
equally attracted to the focus of inflammation, and presumably tend to 
counteract the irritant by some other (extracellular) means. 
8. While to the wandering cells appears to be allotted the main 
duty of removing deleterious and irritant matters, certain of the fixed 
cells of the organism, notably the endothelial cells of the vessels, can 
also exert these functions. 76 
SYSTEM OF MEDICINE 
9. Among the very large number of Metazoan forms in which no 
complete vascular system is present, this attraction of the leucocytes to 
the region of injury is at first the sole response to injury. At a later 
period proliferation of the fixed cells occurs in the neighbourhood of 
the injury. 
10. Among the higher Metazoa, in which there is a well-developed 
vascular system, the determination of leucocytes to the region of irrita- 
tion still continues, and is in fact markedly aided by the participation 
of the vessels in the inflammatory process. 
11. The vascular phenomena in inflammation may be regarded as 
serving two main purposes (a) the pouring out of increased fluid into 
the injured area; (6) the afflux and diapedesis of leucocytes. 
12. Even in the highest Metazoa, possessing fully-developed vascular 
systems, the response to injury in a non-vascular area, such as the 
cornea, may be associated with no change in the surrounding vascular 
areas, but purely with a determination to the injured area of leucocytes 
already free in the surrounding tissues. 
13. The second phase of the inflammatory process, that of tissue 
repair, but very rarely occurs without evidence of previous migration 
of leucocytes and exudation from the congested vessels. 
14. A comparative study leads inevitably to the conclusion that the 
determination of leucocytes to the region of injury is the most constant 
and most characteristic early response to injury recognisable through- 
out the Metazoa, and that it must be regarded as the most important 
factor in the first stage of the inflammatory process. The vascular 
phenomena noticeable in the higher Metazoa must be regarded as a 
second and highly important factor of later development and adjuvant. 
New tissue formation is the prominent characteristic of the later stages 
of the process. 
15. As among the Protozoa, so in the Metazoa, the response to 
injury is consistently an attempt to repair the injury. 
This general survey of the response to injury throughout the animal 
kingdom demonstrates most clearly that the same broad principles, the 
same methods of defence and repair on the part of the organism, are 
called into activity from the lowliest forms to the highest; that, in fact, 
no line can be drawn to separate one set of phenomena as truly inflam- 
matory from another set which, while also a response to injury, are non- 
inflammatory. Although it is true that the term inflammation implies 
a reddening and congestion of the vessels, we find upon closer exam- 
ination that this reddening and congestion is not the fundamental but a 
superadded feature in the process of repair of injury a feature super- 
added as the organism advances in its place in the animal kingdom. 
Thus if we are to comprehend the process satisfactorily we must pass 
beyond the narrower acceptation of the term. 
Having thus sketched broadly the general phenomena of the inflam- 
matory process, it will be well now to describe in fuller detail the factors 
of this process among the higher vertebrata, and to bring together the INFLAMMA TION 
77 
more important results of the study of the respective functions of the 
wandering cells, the vessels, the fixed cells, and the nervous system 
in inflammation. 
PAET 11. The Factors in the Inflammatory Process 
Chapter 1. The Part plated by the Leucocytes 
The Leucocytosis of Inflammation. —As I have already shown, there 
is more than one form of leucocyte in the mammalian organism, 
and the several forms evidently possess different attributes, and act 
differently in the reaction to injury. Inasmuch as these forms have 
been variously classified —so variously, in fact, that it is often far from 
easy to collate the various descriptions, and to discuss the forms distin- 
guished by one observer in the terms of another —it is necessary to 
give the chief classifications of them, and their relations. 
The first to discriminate between the forms of white corpuscles in 
the blood was Wharton Jones so long ago as 1846. He drew a dis- 
tinction between 
A Granule cells \ Finely granular‘ 
Xli AlidllUlu LCIID < /-* i i 
} Coarsely granular. 
B. “Nucleated” cells Non-granular. 
His observations, together with those of Eindfleisch in 1861 and 
1863, were confirmed and advanced by Max Schultze, who made out the 
following forms: 
1. Small round cells with round nucleus and little clear protoplasm. 
2. Larger cells with round nucleus and more clear protoplasm. 
3. Cells with finely granular protoplasm, and one, two, or more nuclei. 
4. Cells with coarse granules in the protoplasm. 
The distinctions drawn were, so far, purely morphological; and very 
little notice was taken of these varieties for a long period until Ehrlich, 
in a notable series of papers extending from 1878 to 1887, drew atten- 
tion to the fact that the wandering cells of the organism react diversely 
toAvards the different aniline dyes and possess diverse tinctorial affinities 
indicating chemical differences in the nature of certain constituents 
of the cell bodies. The granules of the previous observers were found 
to be variously affected by the dyes employed; they were shoAvn not to 
be fatty, but as Ehrlich put it of the nature of a glandular excre- 
tion ;1 and comparing the effects of the two groups of aniline colours 
that in which the dye is associated with the acid constituent of the 
salt, and that wherein the dye forms the base (the “ acid ” and “ basic ” 
1 J. Weiss has studied the micro-chemical reactions of the eosinophilous granules, 
and concludes that they are of albuminoid nature ; as they were found not to be digested 
in gastric juice he would ally them with the nucleins. 78 
SYSTEM OF MEDICINE 
aniline dyes respectively) lie made out the existence of five forms of 
granulation associated with as many varieties of wandering cells. His 
table of cells according to their granulation is as follows: 
a. Granulation Eosinophile. Cells frequently in horse’s blood, present con- 
stantly in small numbers in human blood; numerous in medulla of 
bones of rabbits, dogs, guinea-pigs, etc. Stain deeply with acid aniline 
dyes. Granules large and coarse. 
/3. Granulation Amphophile. Cells frequent in rabbits and guinea-pigs in 
blood; present also in medulla of bones. Stain both with acid and basic 
dyes. Granules fine. 
y. Granulation Basophile.—Large cells found in the connective tissue, 
from the frog upwards, “ Mastzellen ” ; in blood of man only in cer- 
tain cases of Leucaemia, Stain only with basic dyes. Granules 
coarse. 
5. Granulation Fine Basophile.—The “mononuclear” leucocyte of human 
blood. Granulation fine. Stain with basic dyes. 
e. Granulation Neutrophile. The most frequent leucocyte of human 
blood, “ polynuclear.” Stain only in neutral dyes not in acid or 
basic. 
While Ehrlich and his pupils, and Rieder, have done much to throw 
light upon the relative numbers of the leucocytes possessing these different 
granulations in different diseases, they have accomplished little in dis- 
covering the origin of the various forms, their functions, or their relation- 
ships. We owe the first satisfactory studies upon the properties of the 
different forms to Metschnikoff, who, at an early period in his long- 
continued and wonderful series of researches upon Phagocytosis, made 
out that the different wandering cells of the body act differently towards 
microbic and other foreign particles introduced into the organisms. Thus 
he was led to draw a distinction between 
1. Lymphocytes immature leucocytes. 
2. Large hyaline cells, mononuclear, phagocytic, “macrophages.”1 
3. Smaller neutrophile cells, polynuclear, “ microphages.” 
4. Eosinophile leucocytes not phagocytic.2 
Quite recently the admirable researches of Prof. Sherrington, and of 
Hr. Kanthack and Mr. Hardy, have appeared which, starting on the 
groundwork laid down by the older observers, have made a notable 
advance in the determination of the function of the various forms of 
wandering cells in inflammatory and other conditions. The observations 
1 While acknowledging that a certain amount of convenience attends the employ- 
ment of these terms, “ macrophage” and “microphage,” I cannot but agree with Pro- 
fessor Burdon-Sanderson that they are utterly barbaric. 
2 While this article was passing through the press, M. Mesnil, a pupil of Metschnikoff, 
has stated that eosinophilous cells can occasionally act as phagocytes. The statement is 
contrary to Metschnikoff’s previous observations and, I may add, contrary to general 
experience. Until further confirmatory observations have been made, lam not prepared 
to accept the statement. INFLAMMA TION 
79 
of Kanthack and Hardy are especially full, and I shall have occasion to 
refer continually to their results. In the meantime it may be said that 
they materially simplify the classification given by Ehrlich, by dividing 
the leucocytes thus: 
1. Coarsely granular i ... „ 
2. Finely granular | Oxyphile cells. 
3. Coarsely granular I _ ... 
4. Finely granular | Basophile cells, 
5. Hyaline cells. 
Staining with acid dyes. 
Staining with basic dyes. 
6. Lymphocytes. 
Their coarsely granular oxyphile cells are the eosinophile cells of 
most writers; their finely granular are the neutrophile and amphophile 
of Ehrlich. They prove conclusively that Ehrlich’s neutral stain is in 
no sense to be regarded as such, but must be considered as an acid dye. 
It is now possible to collate these various classifications, and in this 
way to begin to study the functions of the various forms with a clear 
appropriation of the terms employed in the following paragraphs. 
Collation of the different Classifications of the Varieties of Leucocytes. 
Kanthack and Hardy. 
Ehrlich. 
Metschnikoff. 
Max Schultze. 
Wharton Jones. 
Lymphocyte. 
Hyaline cell. 
Lymphocyte. 
Lymphocyte. 
Macrophagocyte. 
Small round cell I. 
Large round cell II. 
1 Non-granular 
) nucleated cells. 
Coarsely granular 
oxyphile. 
Eosinophile cell. 
Eosinophile cell. 
Cells with coarsely 
granular proto- 
plasm. 
Granule cells, 
coarsely granular. 
Finely granular j 
oxyphile. 1 
Coarsely granular 
basophile. 
Finely granular 
basophile. 
Neutrophile 
Amphophilc ) 
Basophile cell with 
7 granulation. 
Mastzellen. 
Basophile cell with 
S granulation. 
Microphagocyte. 
Cells with finely 
granular proto- 
plasm. 
Cells with finely 
granular proto- 
plasm. 
Granule cells, finely 
granular. 
? Granule cells, finely 
granular. 
Lymphocyte. Immature leucocyte ; round nucleus deeply staining ; scanty pro- 
toplasm ; increased in number after food; diminished after starvation; 
indistinguishable from small elements of lymphoid tissue. Not phagocytic ; 
variable in number; not amoeboid; may form up to 30 per cent of the 
leucocytes present in human blood. 
Hyaline Cell. Round or kidney-shaped nucleus of slight staining power; 
abundant protoplasm; hyaline; non-granulated; actively amoeboid and 
phagocytic ; rare in blood (2 per cent) ; abundant in coelomic fluid. 
Nuclei have been seen to undergo mitosis. 
Coarsely Granular Oxyphile. Large horseshoe-shaped nucleus (in man) ; rela- 
tively large spherules in protoplasm; highly refractive; staining deeply with 
acid aniline dyes; abundant in coelomic fluid, in serous cavities, in inter SYSTEM OF MEDICINE 
stices of areolar tissue (K and H), and in bone marrow (Ehrlich) ; rare in 
blood (2-4 per cent) ; amoeboid ; non-phagocytic. 
Finely Granular Oxyphile. Smaller than last (in man) ; nucleus branching or 
polymerous, staining deeply; granules very small and spherical; feeble 
oxyphile reaction (Ehrlich’s amphophile reaction in rabbit, neutrophile in 
man, etc.). Abundant in blood (20-70 per cent of all leucocytes) ; absent 
from coelomic fluid; actively amoeboid and phagocytic. The most common 
form of pus cell. 
Coarsely Granular Basophile. When found free in coelomic fluid, round nucleus 
staining very feebly ; spherules large and numerous, stain with basic dyes 
somewhat similar cells are found stationary in connective tissue spaces 
absent from human blood in health ; non-phagocytic. 
Finely Granular Basophile. Spherical; smallest of the wandering cells ; tri- 
lobed nucleus; clear cell substance containing great numbers of fine baso- 
phile dots. Eound in human blood in small numbers (1-5 per cent) ; increased 
after meals. 
From tins description of the character of the various forms of leuco- 
cytes (for which I am largely indebted to Kanthack and Hardy) it will 
be seen that certain forms are characteristically present in the circulating 
blood, namely, the finely granular oxyphile and the finely granular baso- 
phile ; others in the body fluid, namely, the coarsely granular oxyphile 
and coarsely granular basophile; while the lymphocytes and hyaline cells 
are common to both fluids. It must be added that the eosinophile, or 
coarsely granular oxyphile, are also present in small numbers in the 
healthy human blood: it occurs in larger numbers, however, in diseased 
conditions which do not come within the scope of this article. 
Of the origin and relationship of these diverse cells we still know 
very little. As Gulland has pointed out, the blood of the embryo is 
entirely free from white corpuscles. The exact period at which each 
form makes its first appearance has not yet been studied, although in 
all probability such a study would throw a flood of light upon the origin 
of the different orders of cells. 
The most that we can say with fair certainty is that the lymphocytes, 
while representing the larval form of leucocytes in general, are in the 
main derived from lymphoid tissue; that some of them develop into the 
hyaline cells (for, as Sherrington and others have noted, every gradation 
is observable between these two forms); and that what appears to be an 
immature eosinophile cell can often be detected in the peritoneal fluid, 
as also an immature coarsely granular basophile cell (Kanthack and 
Hardy). Beyond this we have not at present advanced.1 Ehrlich’s sug- 
gestion that the eosinophile cells are derived from the bone marrow may 
11 quite understand that sundry observers regard all the various forms of leucocytes 
as modifications one of another. It is true that all emhryologically have the same origin; 
so, for example, have the corpuscles of cartilage and bone, yet this does not make carti- 
lage and bone one tissue. Everard, Gulland, Ruffer, Demoor and Massart, state that all 
transitions are observable between the various forms; I cannot but think that the methods 
of staining employed by these observers were insufficient for these wide conclusions. It 
is interesting to note that these observers, like Kanthack and Hardy, found Ehrlich’s 
amphophlle and neutrophile cells to stain with eosin, i.e. to be oxyphile. INFLAMMA TION 
81 
be partially true, but not entirely; inasmuch as it is difficult to correlate 
the preponderance of these cells in the body fluid with so special and 
local an origin, hlor can the recent observation of Siawcillo, that 
eosinophile cells are abundant in the ray which possesses neither bone 
nor bone marrow, be regarded as favourable to Ehrlich’s hypothesis. 
And again, the observations of Metschnikoff and his pupils render it 
eminently probable that some, at least, of the large hyaline cells are 
derived not from lymphocytes, but from proliferating endothelial cells 
of the lymph and blood-vessels and of serous surfaces. Finally, it is 
noticeable that the cells with multilobate nucleus (the finely granular 
oxyphile), the commonest of the haemal leucocytes, are not to be recog- 
nised in lymphoid tissue: yet, as Sherrington has pointed out, certain 
of their peculiarities, notably the contorted shape of the nucleus, may be 
regarded as acquired, inasmuch as if they be allowed to remain at rest 
in the living state outside the body the nuclei become more spherical. 
Of these varieties of wandering cells not all have, so far, been found 
to bear a part in the inflammatory process: but certain forms appear to 
have distinct functions therein: these are the finely granular oxyphile 
(neutrophile), the coarsely granular oxyphile (eosinophile), and the 
hyaline cells. 
A word should here be said concerning the cells of later development, 
appearing as a result of inflammation giant-cells, llanvier’s cells, and 
Gluge’s corpuscles. Of these the last are evidently leucocytes of the 
hyaline type which have taken up the fatty products of tissue degenera- 
tion; the second colossal cells breaking down with great ease—are of 
doubtful origin. Giant-cells would seem to be of more than one variety: 
some appear to be due to aberrant cell growth, wherein the nuclei 
undergo division without the protoplasm of the cell body following suit. 
The characteristic giant-cells of tuberculosis and chronic inflammation 
may now be said with fair certainty to be plasmodia, in all respects com- 
parable to the masses of fused cells seen to form in the lower animals 
around foreign bodies, and by Kanthack and Hardy around masses of 
bacteria in the lymph of frogs outside the body. The recent observations 
of Borel and of Huenschmann strongly support this opinion. 
Phagocytosis.—ln the case of a very large number of pathogenic micro- 
organisms (so large a number that merely to enumerate them, with the 
names of the observers and of the animals upon which the observations 
have been conducted, makes a list so long that in the bibliographical 
table at the end of this article I give only the more important references, 
and not nearly the complete list), after inoculation into the organism, 
a very considerable proportion are to be discovered, sooner or later, 
within wandering cells which have collected in the region of inocula- 
tion. I have already mentioned more than one case of this nature in 
discussing the comparative pathology of inflammation. Evidently under 
certain conditions one of the functions of certain of the leucocytes is to 
attack and incorporate bacteria. The leucocytes having these properties 
are more especially the finely granular oxyphile (where the injection has 
von. i g 82 
SYSTEM OF MEDICINE 
been into a neighbourhood richly supplied with vessels), the hyaline cells 
chiefly where the microbes have found an entry into the body cavity. 
It is, for instance, the finely granular oxyphile cell which is found in 
overwhelming numbers in an extending subcutaneous abscess, and these 
are seen to contain great numbers of the micrococci. 
The conditions leading to this phagocytosis have been very fully 
worked out by Metschnikoff. He has amply demonstrated that the 
microbes can be taken up in a living condition. Thus, if the Vibrio 
Metschnikovi (a form closely allied to the cholera spirillum) be inocu- 
lated into the anterior chamber of the eye of an immunised animal, within 
a very few hours phagocytes are discovered filled with the small, slightly 
curved vibriones. If now one such cell be isolated, placed in a drop of 
Fig. 1. Resolution of acute infectious disease (relapsing fever), spleen pulp of monkey (Macacus 
erythr.), showing (a) raicrophago, multinuclear, with incepted spirochaetes; (6) solitary, and (o) 
forming dense tangle, (d d) nuclei of splenic tissue (Zeiss, T‘B ocular 4; x 1515 diam.). [Motsch- 
nikoff (51). ] 
broth upon a coverslip, made into a hanging drop preparation and exam- 
ined under the microscope, it is seen that the broth causes the death of 
the leucocyte; while with time, and favourable temperature, the microbes 
proliferate rapidly, and completely fill the corpuscle until it disinte- 
grates; whereupon they proceed to multiply in the surrounding fluid. 
This seizing and incorporation of microbes does not then necessarily 
lead to their death. In certain cases of acute disease there may be 
abundant phagocytosis, and the disease progress nevertheless; the 
phagocytes being destroyed by the products of the incorporated organ- 
isms. This is the case in 'mouse septicaemia, in swine erysipelas, and 
(as has been shown quite recently by Gabritchewski) in diphtheria. As 
M. Roux remarks: “ Ils ont fait de leur mieux en englobant les microbes, 
mais ceux-ci se sont adaptes au milieu interieur des cellules, et ils ont 
triomphes.” 1 
!Roux. Trans. Internal. Congress of Hygiene, London, 1891, ii. p. 120. INFLAMMA TION 
83 
In other less acute diseases, such as gonorrhoea; and in chronic 
maladies of a tubercular nature —in tuberculosis, leprosy, and glanders 
—the bacilli may in certain stages be found within the cells and rarely 
free in the lymph spaces, they appear to be almost parasitic, after the 
manner of the microsphsera previously referred to as infesting the amoeba. 
Fio. 2. Two giant-cells, seen under high magnification (x 1515 diam.) from a rodent, the spermophilc, 
inoculated with tuberculosis, to show stages in the destruction of the bacilli, a, unaltered 
bacillus; h, bacillus staining badly, and with greatly thickened capsule; o, bacillus granular and 
breaking up; de, “ shadows.” [Metschnikoff (51).] 
In these cases it would seem as though the toxic properties of the 
microbes and the antagonising powers of the cells were nearly balanced. 
In tuberculosis, for instance, it is not unusual to find in the giant-cells 
some bacilli which evidently are undergoing degenerative changes, stain- 
ing poorly and irregularly, or but faintly traceable as unstained, translu- 
cent shadows, while elsewhere they are apparently proliferating despite 
their intracellular position.1 
1 It is, however, unsafe to declare in all cases that because a micro-organism con- 
tinues to stain well therefore it was living at the moment the preparation was taken and 84 
SYSTEM OF MEDICINE 
And this equality, or almost equality of the resisting powers of cells 
and microbes, may explain the chronic nature of the diseases above men- 
tioned. Nevertheless, in general, it 
may be stated that there is some rela- 
tionship to be recognised between the 
amount of phagocytosis and the viru- 
lence of the microbe; the more virulent 
the microbes the less the proportion of 
them taken up by the cells; and, as 
Kanthack and Hardy have pointed out, 
the longer the time before the phago- 
cytes come into action. As is the case 
in the unicellular organisms, so in the 
wandering cells of higher animals the 
process of destruction of the included 
microbes can, under suitable condi- 
tions, be seen to be digestive. Sev- 
eral observers have seen the anthrax 
bacillus, in frogs and other animals, 
wholly or in part surrounded by a 
Tig. B.—Phagocytes, macrophage and micro- 
phage, to show stages of digestion and 
destruction of bacilli, from spleen and eye 
respectively of white rat with anthrax. In 
1, part of the bacillus is unaffected, but a 
vacuole has formed around the other part, 
which further has now lost the power of 
taking the stain. In 2, various stages are 
seen, the bacilli passing through the granu- 
lar badly staining, to the vacuolated un- 
stained, until finally but faint “ shadows ” 
are observable (Zeiss ±s, oc. S). [Metsoh- 
nikotf (51).] 
vacuole developed within the leucocyte; and, as an evident result, the 
Fig. 4.—Anthrax of pigeon (an animal but slightly susceptible to the disease) to show stages of 
destruction of bacilli by phagocytes. 1 and 2, macrophages: 1, from exudation from eye of re- 
fractory bird ; 2, from muscle of region of inoculation of bird that succumbed; 2, h, 5, micro- 
phages—all from eye twenty-seven hours after inoculation; aa, unaltered bacilli; b1 b2 b3, bacilli 
becoming more and more degenerated and indistinct; oe, debris of bacilli (Zeiss As, ocular 3).— 
[Metschnikoff (51).] 
portion so surrounded has been seen to become swollen and fainter when 
stained, until it has undergone a veritable digestion and dissolution. 
As with the lower organisms, so with the wandering cells of 
fixed by heat. Thus in pneumonia after the crisis a fair number of diplococci may be 
found within the leucocytes of the expectorated contents of the alveoli, and these may 
stain perfectly well; yet it may be impossible to gain a single growth of the diplococcus 
from the same material. INFLAMMA TION 
85 
the higher, there is an evident attraction, or chemiotaxis, whereby 
these cells pass towards the microbes and their products; and this 
chemiotaxis would also seem in general to be in the inverse ratio of 
the virulence of the microbes. I say in general, for with chemiotaxis as 
with phagocytosis there appear to be exceptions to any uniform law; and 
cases can be brought forward—of diphtheria, for example in which the 
leucocytes, instead of being repelled, are attracted in great numbers to 
the region of inoculation of a most virulent bacillus. 
The chemiotactic properties of the wandering cells have been 
especially studied by Pekelharing, Leber, Massart and Bordet, and by 
Gabritchewski. 
Of the results obtained by these observers the most important are 
that leucocytes are variously attracted towards various substances. Thus 
Leber found that the introduction into the system of finely-powdered 
copper and various compounds of mercury caused an abundant collection 
of the wandering cells around the particles, while powdered gold, silver 
and iron exerted no such attraction. Gabritchewski and A. Schmidt 
showed that the products of bacterial growth in general possessed chemio- 
tactic properties yet more powerful than simple chemical compounds. 
While the degree of positive chemiotaxis is found to vary within wide 
limits, the examples brought forward of negative chemiotaxis exerted by 
bacterial products have so far been very few—so few as to support the 
contention of Dr. Kanthack, that it is very doubtful whether any microbes 
by their products actually repel the leucocytes, though they are capable 
of causing the rapid destruction of the attracted leucocytes, and so of 
rendering the area around the microbes relatively free from wandering 
cells. 
A very good study of the action of bacteria of different degrees of 
virulence can be made by repeating an experiment of Metschnikoff. The 
rabbit is an animal susceptible to the growth within its tissues of the 
bacillus of anthrax. As is well known, there are various means whereby 
the virulence of this microbe can be diminished; so that if cultures of 
the “ attenuated ” bacillus be inoculated into susceptible animals, these, 
instead of causing a fatal disease, induce but a transient local inflam- 
matory disturbance, accompanied by fever, and followed by complete 
recovery. If now a small quantity of a virulent culture of the bacillus 
be inoculated into the one ear of a rabbit, and an equal quantity of an 
attenuated culture into the other, the results are very instructive. 
Within twenty-four hours it can be noticed that an acute inflammation 
has been induced in both ears; in both the vessels round the seat of 
inoculation are greatly congested, but whereas at the seat of inoculation 
of the virulent organism there is a serous inflammation so intense that 
the skin is raised and separated from the subjacent tissues by a clear, 
transparent, reddish fluid which also infiltrates the deeper tissues, in 
the other ear there is not nearly the same amount of swelling and serous 
exudation; the region of inoculation is more opaque and solid. Upon 
more minute examination the serous fluid in the first ear is found to 86 
SYSTEM OF MEDICINE 
contain relatively very few leucocytes; the firmer mass in tfie second is 
composed of a huge aggregation of leucocytes [vid. art. “Anthrax’']. 
Evidently, therefore, the relative number of leucocytes migrating, 
and the quantity of serum exuded, depend very largely upon the inten- 
sity of the irritant; and by the intensity of the irritant, and the 
behaviour of the leucocytes, the forms of the inflammatory process may 
be classified. 
But to the subject of classification I shall refer later. In the meantime 
it is well to sum up the theory of phagocytosis as upheld by Metsch- 
nikoff; and those who see in this phenomenon the all-important factor in 
inflammation and the repair of injury (as also in the production of 
immunity), in order that, having put clearly forward the tenets of those 
upholding the theory, I may the more readily state wherein lies the 
strength and wherein the weakness of the doctrine. 
The theory of phagocytosis as set forth in Metschnik off’slater writings 
may be summed up in the following theses: 
1. That certain of the leucocytes present in the blood and lymph, 
notably the finer granular oxyphile or neutrophile, and the large 
hyaline, are capable under certain conditions of taking up bacteria which 
have gained entry into the system. 
2. That in addition to these the splenic corpuscles, the cells form- 
ing the endothelium of capillaries, and sundry other fixed cells of meso- 
blastic origin, possess the same property, although they exert it to a less 
extent. 
3. That these phagocytes seize upon and destroy living and active 
microbes under certain conditions. 
4. That the more virulent the microbe the less the tendency for the 
leucocytes above mentioned, and for the other fixed cells, to take up the 
bacteria. The less virulent the microbe the more extensive the phago- 
cytosis. 
5. That in addition to this power on the part of certain cells (the 
phagocytes) to take up and destroy certain bacteria, another factor 
has to be called in to explain why the wandering cells of the body 
migrate towards the focus or foci where the micro-organisms have 
gained an entry into the body. This factor is the “ chemiotaxis ” 
exerted by the products of bacterial growth, and by some other substances, 
such, for example, as the products of death of tissue and of wandering cells; 
and experimentally also certain chemical irritants as, for example, turpen- 
tine and mercury. In the case of the virulent microbes the leucocytes 
are not attracted to the focus of infection. There is a “negative” 
chemiotaxis, and thus, in the absence of phagocytosis, the proliferation of 
the microbes takes place without hindrance; whereas the less virulent 
microbes and their products attract the leucocytes, they exert a positive 
chemiotaxis, so that there is a migration of leucocytes through the 
capillary and venous walls to the focus of infection, and the leucocytes 
taking up the microbes tend to arrest the infective process. 
6. That the leucocytes may become accustomed and eventually INFLAMMA TION 
87 
attracted to substances from which at first they were repelled, and thus 
a negative may be transformed into a positive chemiotaxis. 
7. That the cells, having once acquired positive chemiotactic pro- 
perties in relation to the products of any specific microbe, retain and 
transmit these properties through a series of cell generations, the length 
of which varies according to the microbe, the extent of the primary 
reaction, and the idiosyncrasies of the individual. 
8. That, consequently, the cure of zymotic or mycotic disease, 
whether localised or general, and immunity also, are mainly brought 
about by the activity of special cells (the phagocytes), and are prima- 
rily dependent upon the attraction existing between these cells and the 
products of bacterial metabolism. 
9. The process of inflammation is essentially the endeavour on the 
part of the organism to promote the migration of leucocytes, and to 
aid the inclusion and destruction of the irritant. “The essential and 
primordial element of a typical inflammation is a reaction of phagocytes 
against the irritant (agent nuisible).” (14) Or, more fully, “inflamma- 
tion is to be regarded, on the whole, as a phagocytic reaction of the 
organism against irritants, a reaction which at times is accomplished 
by the wandering cells alone, at times with the aid of the vascular 
(fixed) phagocytes, or with that of the nervous system.” 
10. That in rare cases bacteria may be affected if not destroyed 
by extracellular action, by substances derived from the leucocytes and 
dissolved in the surrounding lymph. 
In the terms of this theory, then, phagocytosis is the all-important 
factor in the inflammatory process, the vascular, exudative, nervous and 
other phenomena being auxiliary means whereby the phagocytic pro- 
perties of the wandering and fixed mesodermal cells may be brought 
more fully into action: the determination of leucocytes that I have 
described is almost entirely to be attributed to an endeavour on the 
part of these cells to take up and destroy the irritant. 
It is necessary now to ask to what extent this doctrine is to be 
accepted. Certainly phagocytosis is a factor in the inflammatory pro- 
cess— no antagonist of this doctrine nowadays is prepared to deny 
this but does it occupy the all-important position arrogated to it 
by Metschnikoff ? Metschnikoff himself admits that there are certain 
wandering cells the coarsely granular oxyphiles which never act as 
phagocytes. When powers so great are found to belong to one set of 
leucocytes, is it likely that another set, which is also especially attracted 
to the inflammatory focus, is absolutely devoid of either bactericidal or 
antitoxic function ? Or, to approach the matter from another stand- 
point, let us take a case supplied recently by Gabritchewski from 
Metschnikoff’s laboratory. If a guinea-pig be rendered refractory to 
the bacillus of diphtheria, and if the vulva be cauterised and infected by 
a virulent culture of this bacillus, there resiilts a necrosis of the surface 
layers. On the free surface of the necrosed region lie the proliferating 
microbes; apposed to the under surface of the necrosed area is a large 88 
SYSTEM OF MEDICINE 
collection of migrated leucocytes. In about three days the necrosed 
tissue sloughs off, and recovery and repair ensue. But in this process 
little phagocytosis is observable. The phagocytosis is evidently not 
commensurate with the extent of the inflammation; and if, as Metschni- 
koff urges, the leucocytes are the all-important factor, their powers of 
defence must here include something beyond the incorporation of the 
micro-organisms. The same additional something would seem to be 
wanted to explain the healing of abscesses. 
A crucial test of the importance of phagocytosis has been devised by 
Baumgarten, and repeated, with like results, by Sanarelli. If microbes 
be placed in an animal which has normally the power of withstanding 
the growth of such microbes; and if, further, they be so placed (in 
bags of filter paper, celloidin, or pith) that the leucocytes cannot attack 
them, although the body fluids can easily bathe them, then, if Metschni- 
koff be right, the microbes ought to flourish unaffected. Baumgarten 
and Sanarelli found that this is not so, that the microbes are destroyed 
despite the absence of phagocytes; but Metschnikoff, repeating these 
experiments, obtained diametrically opposite results. Both Baumgarten 
and Sanarelli are capable observers Although it is true that the former 
by the very violence of his attack upon Metschnikoff has materially 
weakened his position. It is, however, difficult to explain away their 
positive results, or to arrive at a conclusion other than that under certain 
conditions the microbes may be destroyed without being ingested. 
The Humoral Theory. The conception that there is some agency 
besides phagocytosis pure and simple has led bacteriologists, in the 
study of phenomena of inflammation and immunity, to engage in a very 
remarkable series of experiments. Although some of them have failed 
to establish a satisfactory theory of immunity, they have led to results 
of such high importance as the discovery of the serum treatment of 
diphtheria and tetanus. The majority of these researches, indeed, 
bear especially upon the production of immunity, and only secondarily 
upon the inflammatory process. It is unnecessary for me, therefore, to 
describe them in detail; it will suffice if I indicate the direction taken 
by the more important among them. 
First in order of time may be mentioned hiuttall’s observations. 
In an attempt to repeat Metschnikoff’s researches upon the destruc- 
tion of the anthrax bacillus, this observer noticed that if he placed 
a fine canula containing a fresh culture of attenuated anthrax bacilli in 
the tissue of a rabbit’s ear, there resulted in sixteen hours a rich cellular 
exudation; but phagocytosis appeared not to reach its maximum for 
twenty-two hours, and even then half of the bacilli lay free and not taken 
up by cells; and he found, further, that the free bacilli showed involu- 
tion and degeneration to the same extent as did the ingested. This led 
him to study the effect of blood serum, defibrinated blood and lymph upon 
the bacilli, and he discovered that these fluids had a remarkably rapid 
action, destroying great numbers within a very few hours. Moritz, 
Traube, Yon Fodor and others, had previously recognised this rapid INFLAMMA TION 
89 
destruction of micro-organisms in the living blood, but Nutt all’s very 
full research appeared to show conclusively that the bacteria-destroying 
power resided largely in the serum, and that in inflammation the exuded 
fluid rather than the leucocytes brought about the destruction of the 
microbes. 
These observations were confirmed and extended by Nissen, Behring, 
and Buchner, and a most valuable series of contributions (see article on 
the “General Pathology of Infection”) have been made by Hankin, 
Buchner, Vaughan, Tizzoni and Cattani, Behring, and others, upon the 
nature and properties of the substances to be derived from the blood 
serum of animals either naturally immune to certain diseases, or rendered 
immune by one or other procedure. What is more, it has been rec- 
ognised that two orders of substances are recognisable: one capable 
of destroying pathogenetic microbes, the other not destroying them, but 
rendering their products inert. 
It would thus at first sight appear that in these discoveries there is a 
direct contradiction to the theory of phagocytosis. Yet upon further 
study this is found not to be the case. 
As was shown by Nuttall, at the commencement of these studies, the 
blood serum removed from the body acts far more rapidly and energeti- 
cally than do the blood plasma and lymph within the body. The dis- 
parity of action between the two is remarkable. Thus Lubarsch has 
shown that in order to kill a rabbit by anthrax, by injection into the 
circulating blood, at least 16,000 virulent bacilli of the disease must be 
introduced: a smaller number produces only a transient disturbance. 
That is to say, the whole circulating blood can only destroy less than 
16,000 bacilli at a time. On the other hand, one cubic centimeter (15 
minims) of rabbit’s blood serum can in a few minutes kill an equal or 
even greater number. 
The Cellulo-Humoral Theory. If the serum and if the blood plasma 
contain bactericidal substances, these must in all likelihood be developed 
by certain cells, and thus at bottom the humoral theory must be cellular; 
and the very fact of the great increase in the bactericidal properties 
of the blood immediately on its withdrawal from the body, must suggest 
that in the changes which occur in the extravascular blood there is a 
liberation and solution of bactericidal substances. Now the first and 
foremost of these changes is the breaking down of the leucocytes 
as the blood begins to clot. It may therefore be that this breaking 
down of the leucocytes, with liberation of their contents, is capable of 
explaining the increased bactericidal action of defibrinated blood and 
blood serum. 
That the leucocytes contain bactericidal substances was first demon- 
strated by Dr. Hankin, who obtained from the lymphatic glands and 
spleens of animals immune to anthrax (dogs and cats), a proteid of the 
nature of a globulin identical with Dr. Halliburton’s cell globulin /3, and 
having a bacteria-killing power similar to that possessed by blood serum. 
In later observations upon the rat he showed that there was a relationship SYSTEM OF MEDICINE 
between the amount and activity of these “ defensive proteids ” and the 
power of resistance of the animal to the disease. Thus Hankin showed 
that in animals possessing the power of destroying bacilli, the organs 
containing the largest collections of leucocytes yielded notable quantities 
of a bacteria-destroying substance. 
For the last few years I have steadily urged this view, and observe 
tion after observation is proving it to be correct. Recently Buchner has 
shown that if sterilised emulsions of the gluten of wheat be injected into 
the pleural cavity of a dog and rabbit, its presence leads to the pouring 
out of an aseptic exudation peculiarly rich in leucocytes, and this exuda- 
tion is more bactericidal than is the blood and serum of the animal. 
Further, Victor C. Vaughan is led to the conclusion that the bactericidal 
action is associated with the leucocytes by his discovery that from 
blood serum a nuclein (or nucleinic acid) can be separated a body, that 
is, which so far has been found exclusively in connection with nucleated 
cells. This nuclein is either itself bactericidal, or has a bactericidal 
substance in intimate association with it; and Vaughan’s observations 
and conclusions have been substantiated by the later and independent 
researches of Kossel upon nucleinic acid. 
Further confirmation of the correctness of these views that the 
bactericidal action of the blood serum is due to the breaking down of the 
leucocytes—has been supplied from the laboratory of Denys at Louvain. 
Denys and Havel have shown that the blood and exudations of the dog, 
freed from leucocytes either by filtration or by centrifugal action, lose 
their bactericidal action, regaining it when the leucocytes are reintro- 
duced. Van der Velde induced an exudation rich in leucocytes by 
injecting into the pleural cavities of rabbits sterilised cultures of the 
pyococci, and killing the animals at various periods. Centrifugalising 
the pleural fluid, he found that the older the exudation, and the richer it 
had been in wandering cells, the more powerful its bactericidal action, 
this being out of all proportion to the bactericidal action of the blood 
serum removed at the same time and similarly centrifugalised. 
But more convincing proof has been gained by a study of the leuco- 
cytes in action. Even in 1887 liibbert, in his studies upon the fate 
of spores of various species of aspergillus and mucor inoculated into the 
anterior chamber of the rabbit’s eye, had found that two stages of reaction 
were recognisable; at first the spores and developing hyphal filaments 
became surrounded by dense clusters of leucocytes, which remained in 
apposition to, but did not ingest the micro-organisms. Nevertheless 
they appeared to bring about a weakening and lowering of vitality on 
the part of the spores and filaments, so that after a time other cells 
could manifest their phagocytic activity and take them up. liibbert, it 
is true, attributed the lowering of vitality to the walling in (“ Wallbil- 
dung”) by the leucocytes, and consequent lack of nutrition; but the fact 
remains that he demonstrated a preparatory extracellular action upon 
the micro-organisms by the leucocytes. 
Altogether the fullest and most important studies upon this extra- INFLAMMA TION 
91 
cellular action have been those of Kanthack and Hardy. In their first 
communication to the Royal Society these observers showed (and their 
experiment can be repeated without difficulty) that if a drop of frog’s 
lymph be placed upon a coverslip, with the addition of a few anthrax 
bacilli, and this preparation be suspended in a moist chamber, an ex- 
amination extending over four or five hours reveals the following suc- 
cession of changes; 
1. The coarsely granular oxyphile cells are strongly attracted to the 
bacilli: they move towards them, and apply themselves to their surface; 
their protoplasm, ordinarily sluggish, exhibits quick streaming move- 
ments. Next the eosinophile granules are discharged, and the bacilli 
begin to show signs of degeneration. During this stage the hyaline 
cells, the phagocytes proper, remain quiescent, and are not even at- 
tracted towards the bacilli. 
2. The hyaline cells proliferate and eventually approach the masses 
of oxyphile cells surrounding the bacilli; they fuse with these forming 
a plasmodium around the chains and for the next hour or two nothing 
can be clearly made out as to the action of individual cells. 
3. The first stage in the dissolution of the mass is the separation 
and wandering away of the oxyphile cells ; next, the hyaline phagocytes 
containing remnants of the bacilli within vacuoles slowly break apart. 
4. A third set of cells, with basophile granules, is observed to 
approach during this last period; as to their functions Kanthack 
and Hardy are a little doubtful. 
Here, then, we have clear evidence of division of labour among the 
wandering cells of the frog: the coarsely granular oxyphile cells act as 
unicellular glands discharging or excreting their granules, and these 
granules dissolving appear to exert a deleterious action upon the bacilli, 
in consequence of which the hyaline cells are now capable of ingesting 
them. I may add that occasionally the coarsely granular cells may be 
seen to act when not in immediate apposition to the microbes; the num- 
ber of granules in a cell may diminish, and at the same time neighbour- 
ing bacilli manifest signs of partial dissolution.1 
Continuing their research Kanthack and Hardy have demonstrated 
these distinctions in the function of the different forms of leucocytes 
throughout the vertebrata up to man. They have shown that in general 
the hyaline cells act as the phagocytes of the lymphatic and coelomic 
system; the finely granular oxyphile (neutrophile and amphophile) as 
the phagocytes of the heemal system; while the coarsely granular 
oxyphile (eosinophile) when present possess excretory functions. 
If capillary chambers filled with bacilli or their products, or some 
irritant such as nitrate of silver or turpentine, were placed under the 
skin, or in the peritoneal cavity, and allowed to remain there for periods 
1 Mesnil, in a long and often suggestive work, which appeared while this article was 
in the press, contradicts these observations of Kanthack and Hardy. Apparently he 
never once attempted to repeat their procedure, never once attempted the simple methods 
necessary to confirm their results. His criticism must therefore be relatively valueless. 92 
SYSTEM OF MEDICINE 
up to twenty-four hours, they were found to contain a multitude of cells, 
chiefly of the coelomic type. If the irritant were situated in such a 
position as to appeal to the blood-vessels of a vascular membrane rather 
than to the cells of the connective tissue spaces, then the cells were those 
of the haemal system. In both cases in the earliest stages there was 
usually found a preponderance of the coarsely granular oxyphile cells. 
Even in cutaneous blisters induced upon themselves, while the main mass 
of cells present in the serous exudation were the finely granular oxyphile 
of haemal origin, the coarsely granular were always more abundant rela- 
tively to the others than in the blood. The rate of accumulation was 
found to vary according to the irritant. Thus, comparing the action of 
the virulent B. anthracis and the harmless B. ramosus upon rabbits and 
guinea-pigs, it was seen that if cultures of these two forms were placed 
within capillary tubes and introduced into the peritoneal cavity, with the 
former only the coarsely granular oxyphile found its way into the tubes 
(even after seven hours); whereas with the latter enormous numbers of 
the hyaline phagocytes had invaded the chambers within two and a half 
hours. In the former case also the total number of invading cells of all 
kinds was very much less than in the latter case; and there was clear 
evidence of the abundant disintegration and dissolution of many of the 
cells. This destruction of a certain number of cells occurred, whatever 
the nature of the microbe introduced into the system ; and, as these 
observers point out, it must profoundly alter the chemical constitution 
of the plasma, and may therefore play an important part in the struggle 
with the bacilli. They observed phenomena of the same nature as those 
of the frog’s lymph, when they placed anthrax bacilli in hanging drops 
of human blister fluid and examined the preparations upon the warm 
stage, noticing here also the rapid diminution of the granules of the 
eosinophile cells. 
Finally, it must be added that Metschnikoff (while misunderstanding 
wholly the drift of these last-mentioned researches) has recently admitted 
that the wandering cells are capable of exerting an extracellular activity 
upon the bacteria. Certain observations of E. Pfeiffer had revealed that, 
under certain conditions, when guinea-pigs have been rendered highly 
refractory to the spirillum of cholera, these microbes when injected into 
the peritoneal cavity are rapidly modified, becoming swollen and spheri- 
cal before any phagocytosis has time to come into play; and this alteration 
was explained by Pfeiffer as due to the fluid secreted by the peritoneal 
cells following upon the inoculation. Without detailing Metschnikoff’s 
criticism of the value of these observations, it will suffice to say that, 
carefully repeating them, he discovered that five minutes after such 
injection the leucocytes in the peritoneal fluid “ polynuclear,” mononu- 
clear, and eosinophilous were surrounded by a layer of spirilla, while 
the lymphocytes and red corpuscles were entirely free from any such 
surrounding. Here in the immediate neighbourhood of the wandering 
cells, the short, curved bacillary forms could be seen to have undergone 
the transformation into globules. Metschnikoff further recognised a clear INFLAMMA TION 
93 
zone, evidently of exuded liquid, between the leucocytes and the spirilla. 
Whether this be a true secretion, or an accompaniment of the death of 
the cells, he is not at present prepared to say. 
In this way Metschnikoff admits that, besides phagocytosis, an extra- 
cellular action of the wandering cells does occur; so that now the only 
point of paramount importance to be agreed upon is the extent to which 
the extracellular activity is manifested intra vitam. Metschnikoff at 
present holds that it plays a very secondary part compared with phago- 
cytosis ; others, like Buchner in Germany, Denys in Belgium, Kanthack 
and Hardy in England, hold that its part is of high importance. Person- 
ally, while holding that phagocytosis has been conclusively proved to be 
of singularly high importance, I cannot but see in this extracellular action 
of active and of disintegrating leucocytes an adjuvant to the former factor, 
and one which under certain conditions is even of greater value to the 
organism in its attempt to neutralise microbic and other irritants. 
Whether the fixed tissue cells of the body have similar “ extracellular ” 
action upon living irritants, or not, is a matter that has not yet been 
ascertained. There are indications that this may be so. 
Summary. Thus, to sum up the facts gathered together in this 
chapter, the chief results of recent researches into the functions of the 
wandering cells, as they affect our knowledge of the inflammatory 
process, would seem to be the following: 
1. That in the higher animals there are several forms of leucocytes. 
2. That a distinction can be made out in the distribution of the 
various forms, some being characteristic of the blood, others of the con- 
nective tissue spaces and of the coelom and coelomic fluid in general. 
3. That the forms of cells accumulating during the inflammatory 
process consequently vary according to the region of injury. 
4. That a variation is to be made out also in the rate of accumula- 
tion of the different forms of cells: the coarsely granular oxyphile 
(eosinophilous), which in the main are pre-existent in the connective 
tissue spaces, being attracted sooner than the finely granular oxyphile 
(neutrophile haemal) and the hyaline (coelomic) respectively. 
5. That a further distinction is to be made out in the mode of action 
of these cells: the coarsely granular oxyphile never act as phagocytes, 
but possess excretory properties; the hyaline and finely granular oxy- 
phile are characteristically phagocytic. 
6. That the accumulation of leucocytes is due in part to migration, 
in part to proliferation in situ. 
7. That under certain conditions (what these are and what their 
relative importance have yet to be more fully worked out) the phago- 
cytes are capable of directly incorporating pathogenetic bacteria. The 
main conditions would seem to be the possession by the bacteria of 
relatively weak irritant or pathogenetic properties, and by the organism 
of relatively strong powers of resistance. 
8. That under other conditions (where, for example, the microbes are 
endowed with fuller irritant properties, or the constitutional resistance is 94 
SYSTEM OF MEDICINE 
lower) phagocytosis may be preceded by an excretory process on the 
part of certain cells, notably the coarsely granular oxyphile, whereby 
apparently the vitality and irritant properties of the microbes undergo 
a diminution. Here again we are as yet ignorant of the exact value of 
all the factors leading to active intervention of these excretory cells. 
9. That the bactericidal and antitoxic action of the blood serum and 
body fluids outside the body is due to the liberation into these fluids of 
bactericidal and antitoxic substances step by step with the disintegration 
of the leucocytes. 
10. That clearly this liberation of bactericidal and antitoxic sub- 
stances by excretion from living cells, and by disintegration, does not 
obtain to the same extent in the fluids within the living body; never- 
theless it does occur, more especially as the result of irritation, and 
its occurrence is fitted to explain those cases in which "the amount 
of phagocytosis observable is not co-extensive with the disappearance 
of the microbic irritants. 
11. That where the bacteria are endowed with great virulence, there 
the wandering cells migrating to the region are both fewer in numbers, 
and, being killed, undergo dissolution to a very considerable extent. 
This dissolution may in itself, by the liberation of bactericidal substances 
into the inflammatory exudation, hinder the proliferation of the microbes 
to a greater or less extent. If, however, the dissolution be unaccom- 
panied by a massing of active leucocytes peripherally around the region 
of irritation, then the microbic irritants may be carried away from the 
inflammatory focus, and induce generalised disease. 
To complete this summary I will here add other conclusions deduced 
from a study of the later stages of inflammation and discussed in a later 
chapter (“Upon the part played by the fixed Cells in the Inflammatory 
Process ”), viz.: 
12. In the later stages of inflammation the growing fibroblasts may 
often be seen to contain leucocytes in process of digestion. Presumably, 
therefore, a certain number subserve nutrition. 
13. Others are, in certain cases, recognisable in the lymph-spaces 
outside the inflammatory focus, containing the debris of dead tissue. 
Emigration can therefore occur as well as immigration. 
14. The process of development of wandering into fixed cells has 
been observed ; but this is the exception, not the rule. 
15. The contrary process of development of wandering cells from 
degenerating tissue (muscle fibres) has also been recorded by more than 
one observer. 
Whenever injury to the tissues leads to vascular dilation there is 
an increased effusion of plasma from the blood. The extent of this 
effusion varies greatly; it varies with the tissue affected, the state 
of the organism, and the quality and nature of the irritant. Dense 
Chapter 2. The Inflammatory Exudation INFLAMMA TION 
95 
tissue permits of little exudation, while loose vascular tissue, under the 
action of an irritant of no great intensity, may undergo great exudative 
swelling. There is, for instance, a peculiar liability in serous and 
cutaneous surfaces (or more truly in subserous and dermal layers), when 
inflamed, to manifest abundant exudation. Their vascularity and the 
slight external resistance would appear to explain this liability. There 
is not the same tendency to abundant exudation from mucous surfaces 
save where, as in the alveoli of the lungs, the epithelium is reduced to 
a single layer of delicate flattened cells; on the other hand there is a 
marked tendency towards serous infiltration and swelling of the sub- 
mucosa. That some general state of the organism is a factor concerned 
is seen when virulent anthrax bacilli are inoculated subcutaneously into 
an ordinary rabbit and into one that has been rendered immune: in the 
former the exudation is of a serous nature, in the latter little fluid is 
exuded from the vessels. The effect of the quality of the irritant is 
observable upon comparison of the results of inoculation of various 
microbes. Some cause little exudation of fluid. These are in general 
of low pathogenic quality, but not always; certain virulent microbes 
(such as those of tetanus) lead, when inoculated, to relatively little 
effusion of fluid from the vessels. On the other hand, it may be stated 
definitely that where in a moderately dense tissue the injection of a pure 
culture of a micro-organism leads to well-marked exudation, the micro- 
organism is of high virulence. 
Can any meaning be ascribed to this effusion ? Is it an attempt 
at increased nutrition in the injured region? It has been sug- 
gested, in accordance with Virchow’s theory of inflammation, that 
the injury, stimulating the surrounding fixed cells, leads to increased 
local metabolism; and that the exudation is a means of bringing to the 
region the increased nourishment demanded by the increased cellular 
activity. But inasmuch as exudation is most marked in those cases 
where there is most profound and rapid cell destruction, and again at 
the early stage of the inflammatory reaction, when evidences of growth 
and proliferation of the fixed cells of the region may be, and most often 
are, wholly wanting, this view can scarcely be upheld. Yet at a later 
period of the process, and again in chronic inflammation, the overgrowth 
of the connective tissue cells would appear to stand in close relationship 
to the over-nutrition caused by the continued dilation of the vessels and 
the pouring out of excessive lymph into the tissues. There is, appar- 
ently, a close relationship between the increased exudation and inflam- 
matory hyperplasia. 
That the exudation exerts a “ flushing out ” action is very evident in 
many cases. Thus the inflammation induced by plunging an animal’s leg 
into hot water is accompanied by great increase in the amount of lymph 
obtainable from the efferent lymphatics of the part. It is shown also by 
the presence of streptococci in the lymph channels outside the area of 
acute inflammation in erysipelas, by the frequent implication of the 
nearest lymph glands in suppurative disturbances, and by the appearance 96 
SYSTEM OF MEDICINE 
of lesions, due to the direct action of bacterial products, in organs 
far removed from the focus of bacterial proliferation in such diseases as 
diphtheria and tetanus, wherein, as a rule, the bacteria remain strictly 
localised. It is clear that the exudation into an inflamed area can accom- 
plish a removal of irritant matters. It is clear also, from more than one 
of the examples given above, that a process Avhich may be beneficial to 
the region of injury may be harmful to the system as a whole. 
It is interesting to note that this effect of flushing, in part beneficial, 
in part harmful, has, if I may so express it, gained a certain amount of 
recognition on the part of the organism. Where the irritant can be con- 
veyed to the exterior an abundant exudative inflammation generally 
occurs —an abundant flushing; where it can be conveyed into one of 
the body cavities the same holds good; but here a mechanism is often 
called into action whereby the exudate with its contained irritants is held 
within the serous cavity for days and weeks after all signs of active 
inflammation have subsided. The organism, that is to say, would seem 
to restrain its draihage to the general lymphatic system. Where the 
irritant is merely the product of tissue change the profuse exudate is 
rapidly conveyed away; where, on the other hand, the injury is of 
bacterial origin, the passage of lymph from the focus of inflammation, 
is, generally speaking, not nearly so free; it is of thicker consistency 
and drains away slowly. In short, as I have already indicated, where 
the microbe is not too virulent a cellular rather than a serous inflamma- 
tion is produced; and in place of abundant flushing an increased anti- 
bacterial and antitoxic action of the exuded lymph comes into play. 
But besides this “ flushing out ” effect the exudation subserves 
another purpose, namely, dilution of the irritant and reduction of its 
injurious properties, so that it acts with lessened force upon the tissues, 
and permits the wandering cells to be attracted to the region where they 
may exert their functions. Where a comparatively mild physical irritant 
leads to abundant exudation the flushing out action appears to be in the 
ascendant, where microbic irritants cause great local inflammatory 
oedema, judging from the less extensive lymph flow from the region, the 
diluent action must be regarded as the more important. I have already 
pointed out that a relation may be traced between the intensity of 
bacterial irritation and the extent of the exudation. In short, there 
may be great exudation under two apparently opposed conditions: in 
the presence of comparatively mild physical irritants, and in that of 
severe bacterial irritants. In the former case it more especially sub- 
serves removal, in the latter dilution of the poison. 
The fundamental distinction between the inflammatory exudation and 
ordinary lymph is its richness in proteids. Whether we regard lymph 
as a filtrate pure and simple from the blood, or, with the majority of 
modern physiologists, follow Heidenhain in regarding it as the result of 
a selective filtration, it is eminently probable that in inflammation the 
exudate approaches in its composition more nearly to the blood plasma 
than does ordinary lymph. The dilatation of the capillaries, the conse- INFLAMMA TION 
97 
quent thinning of the endothelial layer with, it may be, the opening 
of some lacunae between the individual cells, and the direct action of 
the irritant upon these cells, may all be expected to aid the transuda- 
tion. In this way the amount of proteid matter in the lymph may be 
increased. But equally important must be the addition of proteids due 
to the breaking down of leucocytes and tissue cells. I have already 
discussed this destruction of the cells, and need not here give the evi- 
dence of its occurrence. 
In addition to the proteids the inflammatory lymph may contain 
other substances worthy of more than passing note. Of these the more 
important are ferments, the results of proteolysis (notably fibrin and 
its precursors, and peptones), and in many cases mucin, together with 
bactericidal substances, and, where bacteria are present, the products 
of their growth. 
The presence and amount of these substances depend largely upon 
the intensity and character of the inflammation. Thus the total quantity 
of proteids, and the proportion of fibrin, albumin, and globulin present, 
vary within wide limits. The following table1 of observations made by 
Dr. Halliburton shows well this variation in proteids, and the difference 
existing between inflammatory exudations and dropsical effusions; 
Pleural Fluid from 
Sp. Gr. 
Percentage Quantity of 
Total 
Proteid. 
Fibrin. 
Serum- 
globulin. 
Serum- 
albumin. 
Acute pleurisy, Case 1 
,, ,, Case 2 
,, ,, Case 3 
Ilydrothorax . . 1 
Average of three cases f 
1023 
1020 
1020 
1014 
5-123 
3-4371 
5-2018 
1-7748 
0-016 
0-0171 
0-1088 
0-0086 
3-002 
1-2406 
1-76 
0-6137 
2- 
1-1895 
3- 
1-1557 
Between the amount of fibrin present in exudations and the amount 
of peptones there is an inverse ratio. Peptones are especially devel- 
oped in connection with suppurative inflammation; and the more an 
inflammation tends to be suppurative the greater is the breaking down 
of the fibrin, as also of fixed and wandering cells, and the more evident 
the production of peptones, until in chronic abscess-formation of fair 
extent the peptones pass into the general circulation, and are excreted 
and recognisable in the urine. 
Into the discussion of the mode of formation of fibrin I need not en- 
ter here, intimately connected as the subject is with the inflammatory 
process. The greater text-books of Physiology enter exhaustively into 
the matter. Suffice it to say that, as in the blood, a direct relationship 
1 These figures are thoroughly in accord with those of other analyses by Reuss, 
Hofmann, Mehu, and Letulle. 
von. i h 98 
SYSTEM OF MEDICINE 
is made out between the breaking down of leucocytes and the develop- 
ment of this substance in inflammatory exudations. 
It is in connection with inflammation affecting serous and epithelial 
surfaces1 that fibrin is most clearly recognisable, forming, it may be, 
thick coatings of the badly-named “ inflammatory lymph ” over the in- 
flamed surfaces. This deposit is in all respects comparable to the forma- 
tion of thrombi in the blood-vessels. Here, as there, the deposit occurs 
only when the endothelium has undergone destruction and the roughened 
sub-endothelial tissues are exposed. And here also the fibrin may be 
deposited either in filamentous or homogeneous and hyaline form accord- 
ing to circumstances. 
Leaving out of account coagulation-necrosis as not occurring in 
direct connection with exudates, it may be said that similar fibrin for- 
mation is frequently recognisable in connection with primary inflamma- 
tion of parenchymatous tissues.2 
The beneficial effects of fibrin formation in serous cavities have been 
rendered abundantly manifest by the increase in abdominal surgery. No 
one who has followed any considerable number of operations for appendici- 
tis can have failed to remark how, in case after case, despite the intricacy 
of the abdominal coils and their mobility, the strongly irritant matter pro- 
duced by gangrene of the appendix, or oozing through perforations in it, 
is restricted within a relatively small space by the surrounding fibrinous 
adhesions which form rapidly between the intestinal loops. By this means 
alone the peritonitis is restricted and “ regional,” instead of being general- 
ised from the onset. Even when inflammation (as in pericarditis) affects 
the whole extent of a serous cavity, the layer of fibrin acts as a protective 
coat closing the lymphatic stomata, hindering the free absorption of the 
morbid material by the lymph and blood-vessels, and filtering bacteria 
out of such fluid as does find its way through to the tissues beneath. It 
is not a little remarkable to call to mind how case after case of purulent 
pericarditis or purulent pleurisy may be examined in which, despite the 
intense suppurative disturbance in the serous cavity, the tissues at the 
other side of the deposit of fibrin the myocardium or the lung tissue 
show little or no tendency to abscess formation. Let there be primary 
abscess formation or gangrene in the lung, and perforation of the pleura 
and hydrothorax may supervene; pleurisy, however intense, does not 
lead to this unless complicated by other disease. Let there be primary 
or metastatic abscess in the myocardium, then there maybe aneurysm and 
rupture of the heart; yet such rupture produced by extension inwards of a 
purulent pericarditis is of the utmost rarity. Let there be inflammation 
originating in the submucosa of the intestines, as in enteric fever, and 
1 Of epithelial surfaces, more especially those covered by a single cell layer, as notably 
the pulmonary alveoli. 
2 Where there are abundant and distensible lymph channels there extensive clotting 
may be seen in the lymph. This is peculiarly well marked in the contagious pneumonia 
of cattle (contagious pleuro-pneumonia). In acute inflammation of various organs, by 
appropriate methods of staining, similar formations of threads of fibrin, often starting 
from cells as centres, may he observed in the tissue spaces. INFLAMMA TION 
99 
perforation may result; general peritonitis, while often clue to perfora- 
tion, never so far as I can call to mind directly induces that event. 
In all these cases the natural protective layer of the serous surface is 
removed or gravely injured at a very early stage; and the layer of fibrin, 
replacing the serous endothelium, forms an effective barrier. I may add 
that the mucin, extruded so as to form a layer over inflamed mucous 
surfaces, presents a similar protective action. 
Passing now to the ferments and ferment-like bodies present in 
the exudate, I may briefly state that these are not only generated and 
excreted by the pathogenetic bacteria present, but are liberated by the 
breaking down of the wandering cells. Abundant evidence of the exist- 
ence of bacterial ferments capable of acting upon proteids, gelatine, 
sugars, etc., is supplied by the study of the growth of these microbes 
outside the body. That ferments also originate from the wandering 
cells has been demonstrated by Leber, who, placing pieces of copper in 
the anterior chamber of the eye, thereby produced a purulent collection 
devoid of microbes, and showed that the exudate was capable of digest- 
ing proteid matter. 
It would seem, therefore, that, more especially in pyogenetic inflam- 
mation, the removal of dead tissue cells and dead leucocytes may, to a 
large extent, be due to the action of the inflammatory exudations, apart 
from any phagocytic action on the part of living active cells; although 
this also comes often into play. 
Of the bactericidal substances present in the inflammatory exudate 
I have already treated. Here I need only repeat that the researches of 
Kanthack and Hardy, of Denys, and lastly of Pfeiffer and Metschnikoff, 
fully prove that substances capable either of destroying microbes or of 
hindering their growth are present therein. 
Summary. To sum up what is known concerning the inflammatory 
exudate, it may be said 
1. That the exudate varies in amount and in character with (a) the 
nature and intensity of the irritant, (b) the condition of the organism, 
(c) the region of irritation. 
2. That while it undoubtedly augments the nutrition of the affected 
region, increased nutrition at the early stage of an acute inflammatory 
process would not seem to be of benefit or to play any important part. 
At a later stage and in chronic inflammation the increased nutrition in 
all probability aids the hyperplasia. 
3. That in many cases the exudate exerts a beneficial action by 
flushing out the injured area. 
4. That the exudate plays an important part in diluting the irri- 
tant. 
5. That the development of fibrin in certain inflammatory exudates 
is associated with the breaking down of the wandering cells, and is of 
manifest benefit in so far as it circumscribes the inflamed area, and 
prevents the passage of morbid material outwards. 
6. That the exudate may possess digestive functions, causing the pro- SYSTEM OF MEDICINE 
duction of peptones; the ferments being developed from the cells alone 
when the exudate is aseptic, from these and the microbes together where 
pathogenetic microbes are present. 
7. That the exudate may further contain substances, generated by 
the cells, capable of hindering bacterial growth, and of destroying 
pathogenetic microbes. 
Chapter 3. The Part played by Blood-Vessels 
The study of the action and function of the leucocytes in inflamma- 
tion has profoundly modified our conception of the inflammatory process. 
When the leucocytes were regarded as purely passive agents, and their 
diapedesis as purely secondary to modified conditions of the blood cur- 
rent and of the vascular walls, the theory of Cohnheim was that most 
generally accepted. And this theory regarded the changes in the vessels 
as of the first importance. Thus it was that for several years our atten- 
tion was mainly concentrated upon the determination of the various 
changes of the vessel walls, and of the mechanism whereby these changes 
were brought about. Nowadays less attention is directed to this side of 
the inflammatory process, and it may be said that during the last ten 
years little advance has been made in determining the mechanism of the 
dilatation that accompanies inflammation. 
The subject, indeed, is beset with difficulties. It is most difficult 
to observe the changes that occur in the cells forming the endothelium 
of the congested vessels ; we are still, for instance, far from being sure 
whether the opinion of Arnold is correct, namely, that the leucocytes, 
and, it may be, a large portion of the exuded plasma, find their way out 
through the dilated stomata between the endothelial cells; or whether 
the leucocytes pass directly through these cells as one soap bubble may 
be passed through another. And when we come to discuss whether the 
inflammatory exudation be a filtration, or whether, on the other hand, it 
be more of the nature of an excretion, or what may be termed a selective 
filtration certain components of the blood plasma being permitted to 
pass through, while others are withheld —we are met with the difficulty 
that, of the extravasated leucocytes, a varying proportion undergo rapid 
destruction and dissolution. Thus, in analysing the inflammatory 
serum, we are not dealing simply with the extravasated fluid, but with 
a fluid which in addition contains proteid and other constituents derived 
largely from broken-down white corpuscles, and in part, it may be, from 
the modified cells of the inflamed area. 
Though Arnold’s observations upon the altered condition of the 
vascular endothelium in inflammation appear at first very convincing, 
upon further study they seem at most to indicate that with dilation 
of the vessels there is an increase in the size of the spaces between the 
endothelial cells. They do not, however, prove that these are other than 
virtual spaces filled with intercellular substance; and indeed Arnold 
himself came eventually to the conclusion that some such substance was INFLAMMA TION 
present filling them. The fact that viscid, gelatinous substances injected 
into the circulation may be detected passing through these stigmata is 
not a proof that the spaces are actual; all it proves is that the walls 
are weaker in these regions: it must be remembered that increased 
force and increased intravascular pressure are necessary to promote the 
passage of the injected mass along the vessels. The passage of the mass 
through the walls may therefore be an “artefact.” 
There is this further difficulty in the assumption that these are actual 
spaces that in acute inflammation the exuded fluid in general contains 
a smaller quantity of proteids than does the blood plasma. It is true, 
no doubt, that the stigmata are so small they may possibly act like the 
pores of a filter, and consequently may not permit the free passage of 
certain constituents of blood plasma. Yet, granting all this, if the same 
principles be in action as those governing the ordinary (non-inflamma- 
tory) transudation, we must, with Heidenhain, be inclined to regard the 
endothelium as playing not a passive, but an active role. To enter into 
the large subject of the nature of lymph would be to pass too far afield; 
recent researches, on the whole, favour the view that the inflammatory 
exudation is not a mere filtrate, but is the result of a selective activity 
on the part of the endothelial cells. 
We have not a little evidence that these cells play an important part 
in the vascular phenomena of inflammation. To their power of taking up 
microbes and acting as phagocytes I have already referred; into their 
connection with the slowing of the blood stream I shall enter later. 
Here I would point out that microscopically these cells can be seen to 
alter during the inflammatory process; they become enlarged and 
project into the lumen of the smaller vessels, and in my experience this 
enlargement affects not only the cell bodies, but also the nuclei, which 
at the same time would seem to contain more chromatin and to stain 
more intensely. In cases of chronic inflammation the enlargement is 
followed by proliferation, notably in the arterioles and capillaries, a 
process which may lead to the ultimate occlusion of these small vessels. 
And in acute inflammation, according to numerous observers, mitosis is 
to be seen occurring in these endothelial cells at an earlier period than 
in the surrounding tissues. 
A further and very important process intimately connected with the 
proliferation of the endothelium of the capillaries is the formation of 
new vessels as the result of continued inflammation. It is true that 
Eindfleisch and others have described this as being brought about by 
vaso-formative cells situated externally to the vessels; and that others 
have advanced so far as to suggest that there are cells in the newly- 
forming granulation tissue which become hollowed out and gain attach- 
ment to the pre-existing capillaries in a manner wholly similar to that 
observable in the vascular zone of the chicken embryo. I have sought 
for such intracellular development, but never have I seen the slightest 
indication thereof; nor again have I been able to discover cells 
arranging themselves after the method described by Eindfleisch in 102 
SYSTEM OF MEDICINE 
columns or parallel rows preparatory to the passage of blood between 
them and to the formation of a capillary. 
The search for the earliest signs of new capillaries is a matter of 
peculiar difficulty. I will not peremptorily state that Eindfleisch mis- 
took an arrangement of cells not unfrequently seen in granulation tissue 
for stages in the development of new vessels. I will only say that my 
own observations coincide with those of Arnold, and of the majority of 
those who have more recently studied the question, and lead me to regard 
the formation of new capillaries as originating from the endothelium of 
the vascular loops already in existence. 
The first step in the process is often recognisable, in cases of pleurisy 
and pericarditis, in the projection of loops of pre-existing capillaries 
beyond the line which indicates where the serous endothelium used to 
be, and into the fibrinous clot now adherent to the sub-endothelial layer. 
Such loops are markedly distended, and “point,” as it were, at right 
angles to the denuded surface. A similar pointing or giving way of the 
wall along the convex margin of the loop is also to be made out not 
unfrequently in newly-developed capillaries. In these there is not, as 
might be expected, a thinning of the endothelium along this outer mar- 
gin, but certain of the cells on the contrary appear large and active. At 
times a small sharp protrusion of the vessel wall can be detected in the 
region of pointing. This is best seen in the capillaries that are them- 
selves but newly formed, and composed of nothing but a layer of endo- 
thelial cells. In this layer the protrusion can be made out to be in 
direct continuity with the endothelial cells of the region. At first it 
is solid, but in the later stages it can be seen to be nucleated, and to be 
growing by proliferation of the endothelial cells which thus jut out- 
wards. Even before any further change is noticeable in this projection 
from the capillary wall it may be seen to be united with a similar pro- 
cess originating from a neighbouring vascular loop. Finally, it would 
appear that the joined processes become hollowed out, and thus are 
developed into fully-formed capillary loops. It seems impossible to 
make precise observations on the phenomena of new vascular formation 
in its successive stages. I can but state that these appear to be the 
steps of the process. By what means the new vascular projections join 
together to form loops we are ignorant. Metschnikoff suggests that 
there must be an attraction between the neighbouring projections a 
chemiotaxis leading them to come into apposition; this, however, is 
no more than a suggestion. That they do join is very clear to those who 
have studied granulation tissue, or have observed the vascular network 
connecting the previously separated surfaces of a wound. 
A further function of the vessel walls is to be seen in the slowing of 
the blood current. It is difficult, and in fact impossible, to explain this 
slowing by altered diameter of the arteries and veins. The alterations 
observed in the diameters of the vessels of the inflamed area are such as, 
acting alone, would led to increased rate of flow. Nor again is the 
apparent amount of exudation, and of lymph flow from the affected IN FLA MM A TION 
103 
part, sufficient to make it probable that (as Wharton Jones first suggested) 
the slowing is in the main due to the concentration of the blood, relative 
drying of the corpuscles, and consequent increase of friction: while this 
may be an adjuvant we must, I think, find some more potent factor. 
What this factor is was pointed out long ago by Lister, who, in 1858, 
noticed that coincident with the slowing of the blood stream, the cor- 
puscles move sluggishly along the vessel wall as though attracted by it. 
Lister essayed to prove this by an experiment performed previously by 
Weber. He ligatured a frog’s leg, then irritated a portion of the web by 
a little mustard, and found that, although the blood current had ceased, 
there was nevertheless an accumulation of corpuscles in the vessels of the 
irritated area, the corpuscles gliding into the affected region and becom- 
ing adherent there. Other observers have shown that this accumulation 
is not due to increased adhesiveness of the red corpuscles, inasmuch as 
similar slowing and stasis may be induced if the blood of the frog’s leg 
be replaced by milk and the web irritated. In this case there is a 
gradual slowing of the stream of milk and accumulation of the fatty 
globules in the inflamed area. While in Lister’s experiment the transu- 
dation of the plasma might explain the accumulation of the corpuscles, 
in this latter instance, as in ordinary inflammation, the observed transuda- 
tion is insufficient to account for the accumulation and slowing. Although 
I cannot accept his experiment as conclusive, I am forced to concur with 
Lister to this extent, that in inflammation the endothelium of the vessel 
walls becomes altered, the cells becoming enlarged. With this, as evi- 
denced by the conduct of the white corpuscles, they become more 
adhesive, and this adhesiveness with the associated increased friction 
between the vascular walls and contents I regard as the first factor in 
bringing about the slowing of the blood stream. Let the current once 
accelerated be rendered slower by this increased friction, then transu- 
dation may accentuate the accumulation of corpuscles. 
Summary. While there is very much yet to be learned concerning 
the part played by the blood-vessels in inflammation, and while our 
present knowledge of this branch of the subject can only be regarded 
as very imperfect, the following may, I think, safely be said to epitomise 
what is known at the present time : 
(1) That the vascular walls, and more especially the endothelial cells 
lining the capillaries, play an active and not a passive part in the in- 
flamed area. 
(2) These cells have the power of throwing out pseudopodia and 
of taking up non-motile bacteria. 
(3) They are larger and more prominent during inflammation than 
they are under conditions of health. 
(4) From them are developed the new vascular loops in cases of 
more chronic inflammation. 
(5) They would seem to become more adhesive in inflammation, and 
by this, in the first place, to lead to the adhesion of the leucocytes and 
red corpuscles to their walls. 104 
SYSTEM OF MEDICINE 
(6) Similarly they would seem to cause an increased resistance to the 
passage of the blood current, and in this way tend to slow the rate of 
blood flow. 
(7) The slowing of the stream may further be aided by the passage 
through the walls of increased amounts of fluid from the blood. 
(8) It is impossible by analysis of the inflammatory exudation to 
determine whether this be a mere filtrate or be the result of a selective 
activity of the endothelium. On the whole, taking into account the 
observations made upon ordinary lymph, the latter would appear the 
more probable. 
Other properties of the blood-vessels in respect of inflammation will 
be better discussed in a later section in connection with the discussion 
of the part played by the nerves. 
Chapter 4. —On the Passage oe Corpuscles out of the Vessels 
By his researches, Cohnheim (1867) forcibly attracted the attention of 
pathologists to. the diapedesis of leucocytes in inflammation a process 
which had already been described years before by Addison (1843) and 
Waller (1846) in England; and yet earlier (though without grasp of the 
connection between the diapedesis and inflammation) by Dutrochet, in 
France (1828). Cohnheim recognised the amoeboid nature of the leuco- 
cytes, and saw that once outside the vessels they moved actively, but 
eventually he could not discover that their penetration of the vessel walls 
was anything but passive; and this failure on his part to recognise the 
true nature of diapedesis confirmed him yet more strongly in the view 
that the all-important factors in the inflammatory state were the changes 
in the vessel walls, and, it may truly be said, arrested his advance 
towards a fuller comprehension of the subject. 
It must be acknowledged that there is much which would seem to 
support this view of the passivity of the leucocytes. No one is pre- 
pared to attribute active movements to the red corpuscles, nevertheless 
in inflammation a certain number of these escape through the vessel 
walls. In the inflammation affecting some organs, notably the lungs, 
the number effecting a passage is very considerable. If, then, the red 
corpuscles emerge passively, why should not the emergence of the white 
be passive also ? Add to this the very important observations made by 
Cohnheim, that where the circulation is arrested by compression of the 
artery there diapedesis ceases. This, if invariably true, would seem to 
indicate that when once by changes in the vessel the leucocytes adhere 
to the wall, the further passage through that wall is due to the vis a 
tergo of the blood pressure. 
This, however, is not a safe deduction to draw from the experiment re- 
ferred to. When the artery of an inflamed area is compressed the stoppage 
of the blood stream not only reduces the pressure, but also affects the 
quality of the blood and the conditions of the vessel walls; moreover, it 
must profoundly affect the vitality and activity of the contained leucocytes. IN FLA MM A TION 
These considerations alone render the experiment valueless as a proof of 
the passive nature of the diapedesis. Again the passage outwards of red 
corpuscles does not occur in the earliest stages of reaction to irritation; 
it never precedes the diapedesis of the leucocytes (save where there is 
gross injury), but follows it. A capillary or small vein in the inflamed 
frog’s web, for example, may be seen wholly filled with corpuscles, the 
peripheral zone being quite annihilated, and numerous red corpuscles 
lying in immediate contact with the walls; nevertheless at first leucocytes 
only are seen to emigrate. This difference must be due to some special 
property of these cells. The leucocytes in the blood stream are not 
necessarily globular passive agents, but they are capable of independent 
movement. Leber, in his long series of studies, has pointed out that if, 
with due precautions, a hooked glass tube (closed at its outer end where 
it catches into the incision in the wall) be inserted into a large vein 
no thrombosis may be set up around the intravascular portion, and yet, 
upon removal, a large collection of leucocytes may be found in the tube, 
attracted by a drop of mercury placed within it, with normal salt solu- 
tion. (Mercury is a substance which within the tissues leads to an 
accumulation of leucocytes.) Here, then, there must be active attrac- 
tion and active movement of the leucocytes within the blood stream. 
And Lavdowsky has described very exactly what other observers had 
also noted, namely, that in inflammation the leucocytes in the outer zone 
of the blood stream do not simply adhere passively to the wall, but move 
backwards and forwards before they attach themselves and emigrate, as 
though seeking for a point of less resistance. At times this movement 
is in a direction opposite to that of the blood current. 
If, then, both within and without the vessels, the leucocytes can be 
actively amoeboid, it is strange that they should be passive in the pro- 
cess of diapedesis which to the eye has so characteristically amoeboid 
an appearance. 
As above stated, the compression of the artery passing to an in- 
flamed area is in most cases sufficient to arrest diapedesis in that area, 
and I have suggested that this arrest may be due to the altered envi- 
ronment of the leucocytes. Now, if an embryonic form be taken, in 
which the tissues would seem to possess greater inherent vitality coupled 
with less sensibility, the arrest does not necessarily occur. Thus, 
Metschnikoff has noted that diapedesis of the leucocytes can be fol- 
lowed in the tadpole’s tail after the animal has been curarised to such 
an extent that the heart has ceased to beat and the blood in the capil- 
laries has been brought to a standstill. 
It is evident, therefore, that with our present knowledge we must 
regard the diapedesis of the leucocytes as an active migration, and must 
look upon the blood pressure, the disposition of the blood stream, and 
the altered condition of the endothelium of the dilated vessels as adju- 
vants in the process. The slowing of the blood stream and the diminished 
pressure in the inflamed capillaries render it more easy for the leucocytes 
to accumulate close to the vessel wall; the dilation of the vessels and SYSTEM OF MEDICINE 
consequent thinning of the walls, with the opening, perhaps, of larger 
spaces of cement substances or stigmata between the individual endo- 
thelial cells, render it more easy for the leucocytes to accomplish the pas- 
sage ; but the movement from within the capillaries to the tissue-spaces 
outside is an active process due to amoeboid movement of the leucocytes 
themselves. The continuity of the vessel wall once destroyed, other 
cells red corpuscles may be pressed passively through the walls. 
If this view be accepted, we are bound to look beyond Cohnheim’s 
limit of changes in the vessel wall for the stimulus which, originating in 
the area of irritation, acts upon the vessel wall and the leucocytes in 
contact with it; and, having first set up changes in the former, so reacts 
upon the latter that they emigrate; or, to put it in other words, are at- 
tracted out of the capillaries towards the focus of irritation. It has 
already been shown that the movement of wandering cells in the tissue is 
due to the attraction of a diffusible product of bacterial growth and of 
tissue change, and of sundry organic and inorganic materials a force to 
which the name of positive chemiotaxis has been given. This chemiotaxis 
must be invoked to explain the active emigration of the leucocytes from 
the capillaries, and again to explain its cessation under other conditions. 
Thus, while the exposed mesentery of a frog is a tissue in which diape- 
desis can be observed with facility under ordinary conditions, if it be 
washed with a weak solution of quinine the leucocytes in the vessels 
remain globular, cease to adhere to the walls, and do not emigrate. This 
fact, first noted by Binz, has been confirmed by several observers, among 
whom Disselhorst made out also that, if these same leucocytes be re- 
moved from the vessels, they exhibit their usual amoeboid movements. 
The quinine has not paralysed them, as Binz supposed; but, as Metsch- 
nikoff pointed out, it has neutralised the previous positive attraction, a 
negative or repulsive chemiotaxis being brought into play. It is diffi- 
cult to see how the above facts can be otherwise explained. 
The view that diapedesis is an active process gains further support 
from, and at the same time explains certain interesting observations 
made by, Bouchard, Eoger, and Buffer. These observers have independ- 
ently shown that in sundry instances the results of local injection of viru- 
lent cultures are greatly modified if, shortly before or coincidently, the 
microbes and their products are introduced into the circulation. Thus, 
as Buffer points out, a drop of the culture of the bacillus pyocyaneus in- 
oculated into the anterior chamber of the rabbit’s eye leads ordinarily 
to a great migration of leucocytes to an acute purulent inflammation. 
If, however, the toxins produced by this microbe have previously been 
injected into the circulating blood, no accumulation of leucocytes follows 
inoculation into the eye. Dr. Buffer has also extended most suggestively 
certain observations of Boger. Subcutaneous or intramuscular inocula- 
tion of the rabbit with the bacillus of symptomatic anthrax leads to the 
production of a local abscess with extensive accumulation of leucocytes. 
After simultaneous injections of fluid containing virulent bacilli and 
their products into the vein of the ear and the muscles of the hind leg, INFLAMMA TION 
107 
Buffer found the rabbit dead, within fifteen hours, with a huge tumour 
in the inoculated limb. Here, upon examination, the muscle fibres 
were found widely separated by exudation fluid, in which there had been 
great multiplication of the bacilli; but leucocytes were entirely absent. 
In both of these cases we have therefore diapedesis and determination 
of leucocytes following the purely local action of the toxin; want 
of diapedesis and absence of leucocytes when the toxin at the same 
time circulates in the blood stream. If any large proportion of the 
leucocytes which find their way to a focus of irritation emerge from the 
blood stream, these divergent results are only to be explained by some 
theory which is capable of reconciling the difference in the action of the 
leucocytes when they are circulating in normal and toxin-containing 
blood respectively. 
How, the results in these two cases are entirely consonant with what 
we know concerning the sensitiveness and reaction to stimuli not only 
of unicellular organisms, but also of the higher animals. Organisms, 
whether lowly or of most complex development, only perceive and react 
to alteration in their environment when the alteration exceeds a definite 
ratio. Thus, as Pfeffer has pointed out, a motile bacterium (the “B. 
termo ”) is attracted towards solutions of peptone : if it be already in a 
peptone solution, in order for it to be attracted towards and move into 
a more concentrated solution, this last must be five times as strong as is 
the former. The only possible explanation that I can see of the above 
observations of Buffer and Boger is that the passage and want of passage 
of the leucocytes out of the vessels depends upon the ratio of diffusible 
bacterial products present in the blood stream and in the tissues respec- 
tively. Where the products are localised at one focus in the tissues, 
the leucocytes are attracted out of the unaltered blood, and there is 
active diapedesis ; where there was already a solution of the bacterial 
products in the blood, the ratio of difference between the percentage 
amount of toxin in blood and tissue may be insufficient to stimulate the 
leucocytes; no diapedesis then ensues. 
As is well shown in the experiment with symptomatic anthrax, the 
presence of the bacillus and its products in the circulating blood did not 
prevent inflammation at the region of local injection ; inflammation and 
exudation were abundantly manifest —there was, in fact, a more extensive 
exudation than ever. The irritant that is to say, the toxic products 
of the bacilli at the point of injection was in no wise hindered from 
exerting effects upon the fixed cells of the vessel walls, and promoting 
all the changes in calibre and condition of the walls and in the blood 
stream characteristic of inflammation. But with vascular changes, if 
anything more prominent than in the case where local inoculation alone 
had been practised, the leucocytes stayed within the vessels : now the 
only cause to which we can attribute this abstention of the cells from 
emigration, is lack of attraction certainly not lack of vascular change 
or lack of blood pressure. 
/Summary. lam thus led to the following conclusions regarding SYSTEM OF MEDICINE 
the passage of cells out of the blood stream into an inflamed 
area: 
1. The diapedesis of the leucocytes is, as the name implies, an active 
and not a passive process; it is due to active amoeboid movements on 
the part of the cells. 
2. The stimulus leading to diapedesis is that of positive chemiotaxis. 
It is the attraction exerted upon the leucocytes by the diffusible sub- 
stances associated with the irritant. 
3. Irritants, if themselves diffusible, or the diffusive substances 
developed while the irritants are within the tissues, are capable of two 
separate actions : one direct upon the vessel walls, leading to vascular 
changes ; the other through the walls upon the leucocytes, whereby 
emigration may be induced. 
4. These two actions need not (and frequently do not) manifest them- 
selves pari passu. 
5. In relation to diapedesis, the dilation of the vessels, the altered 
rate of blood stream, the altered disposal of the corpuscles in the stream, 
and the modified endothelium, may all be regarded as adjuvants. 
6. The passage of red blood corpuscles from the blood-vessels into 
the inflamed area is passive, due to the blood pressure and to lack of con- 
tinuity of the vessel walls. Such lack of continuity is afforded in many 
instances by the migration of the leucocytes through the walls. 
Chapter 5. On the Part played by the Nervous System 
If the vascular changes in inflammation were due to reflex influences 
proceeding from the central nervous system, and were in fact controlled 
by the centres in the brain and spinal cord (as has been held by the 
supporters of neuro-humoral theories) then, in the first place, there 
should be a rapid and almost immediate response on the part of the 
vessels of any region on the introduction of an irritant. But this is 
not by any means constantly to be observed. Thus, as Cohnheim 
pointed out, if croton oil be rubbed upon a rabbit’s ear more than an hour 
may elapse before the first beginnings of hypersemia can be detected; 
yet the inflammation eventually set up may be very intense. In the 
second place, section of all the nerves passing to any region of the 
body should have this effect, that injury in the region in question should, 
be unaccompanied by the ordinary vascular reaction. But this is not the 
case. Divide all the nerves which supply a rabbit’s ear for example, and 
then injure that ear, either by heat, cold, or inoculation of pathogenetic 
micro-organisms, and inflammation manifests itself with all the stages 
recognisable in an ear with intact nerve-supply. The vascular changes 
which accompany inflammation can occur then independently of any 
central nervous influences. 
We can proceed farther, and state that regions deprived of their 
nerve-supply are peculiarly prone to inflammatory changes. But this 
liability to inflammatory disturbances in such regions is not directly due INFLAMMA TION 
109 
to the destruction of vase-motor tracts and the cutting off of central 
influences from the vessels of the part, but is, it would seem, immediately- 
connected with the loss of sensation. Divide the ocular branch of the 
fifth nerve of a rabbit, and, if the eye be not protected, ulceration and 
necrosis of the cornea manifest themselves in the course of a few days. 
Protect the eye, either by bringing the lids together or by placing a 
shade over it in such a way that dust and foreign particles are prevented 
from settling upon the surface, and no such ulcerative disturbance mani- 
fests itself. Prom this it is clear that the primary cause of the inflam- 
mation is not any trophic change in the region, but is the lack of sensa- 
tion, whereby irritant substances are permitted to gain a lodgment upon 
the outer surface without any attempt being made to remove them. 
That, in addition, there is a lowered vitality in parts deprived of their 
nerve-supply, and that this renders those parts a more favourable seat 
for inflammatory disturbances is more than probable; nevertheless, this 
would not seem to be the primary cause of the increased liability to 
inflammation. [ Vide art. on u Nutritional Retrogressive Changes.”] 
This, then, in the first place, is clearly recognisable—that the vascular 
changes accompanying inflammation can occur independently of central 
nervous influences. Hence it follows that there must be a peripheral 
nervous mechanism controlling the vessels. It remains, therefore, to 
determine the nature of this peripheral mechanism: is it wholly under 
the guidance of peripheral nerve cells situated in the vessel walls, or 
is it, in part at least, idiopathic ? In the present state of our knowledge 
the answer to this question must be guarded. The more carefully the 
innervation of the various regions is studied, the more clearly is it 
demonstrated that throughout all the tissues of the body there exists 
a wonderfully fine and complicated network of nerve filaments with 
occasional isolated ganglion cells. Yet proof is wanting that this system 
in connection with the vessels is sensorimotor. Indeed, so far as regards 
the heart and ventricular muscle (which may be looked upon as the 
region of the vascular system wherein the motile portion of the walls 
has become specially developed), the researches of Romberg and His lead 
rather to the conclusion that the peripheral nervous system subserves 
sensation alone. 
Dr. H. J. Berkley’s careful series of researches recently brought 
■together in a Johns Hopkins Hospital Report (Neurology 11., 1894) 
throws much light upon the termination of the nerves in various organs, 
and upon the relation of these nerves to the vessel walls. Berkley 
finds in connection with the ventricular muscles a dense network of nerve 
filaments, with small bulbous terminations upon the individual fibres. 
These observations, it must be admitted, tend to weaken the belief in the 
idiomuscular, or, more truly, idioneural action of the heart muscle. 
At the same time, the more the activity of the various tissues is 
studied, the more fully it is seen that many cells retain what may be 
termed reminiscences of an earlier and more embryonic condition in 
Which their functions were varied and less specialised. There is an SYSTEM OF MEDICINE 
inherent probability that the endothelial cells can react directly to stim- 
uli, and that they are capable of idiopathic contraction and expansion 
on appropriate stimuli. We have seen that these cells are capable of 
taking up microbes, and thus seem to exhibit an independent activity 
similar to that observed in the amoeba or the wandering phagocyte. If 
these cells, then, are capable of throwing out pseudopodia, and thus of 
enclosing nou-motile bacteria, are they not capable of contracting and 
expanding, as a whole, according to the stimulus of altered environ- 
ment ? As a matter of fact, such contractility of the endothelial walls 
of the capillaries has been demonstrated by Klebs and Severini. I can- 
not but conclude, then, that the endothelium of the capillaries is to some 
extent self-regulative or neuro-muscular. It is quite possible but 
“ non-proven ” that the muscular coats of the smaller arteries are 
likewise capable of self-regulation, and respond directly to stimuli. 
This view that the vascular phenomena of inflammation can occur 
independently of the central nervous system and of the peripheral nerves 
does not imply that the nervous system, central and peripheral, is 
without its influence upon the process ; far from it. We have evidence, 
in the first place, that the state of the vascular walls is modified after- 
destruction or severance of the nerves. Ido not here refer only to the 
consequent alterations in calibre of the vessels, but also to the changes 
in other properties. Thus Gergens, and to a less extent Etitimeyer, 
noticed that after destruction of the spinal cord the blood-vessels of the 
frog permit a larger quantity of fluid, and even particles of granular 
colouring matter, to permeate them. 
In the second place, we have evidence that the central nervous 
system exercises some direct influence upon the inflammatory process. 
From Cohnheim onwards it has been a matter of common observation 
that when all the nerves of a part have been severed, the stages of the 
process succeed each other with greater rapidity. It may be that the 
modified state of the capillary walls, noted in the preceding paragraph, 
is capable of accounting for this fact, and that, in the absence of central 
influences, dilation of the vessels and exudation of fluid lead to the 
cardinal symptoms of redness and swelling, with associated changes in 
the tissue, at an earlier period. 
Of the part played by the different sets of nerves the external ear of 
the rabbit again furnishes an excellent study. This part has a double 
nerve-supply through the auriculars (major and minor) passing from 
the cervical plexus and the sympathetic branches proceeding from 
the superior cervical ganglion: stimulation of the former leads to 
dilation of the ear vessels, of the latter to contraction of the same. If, 
as shown by Samuel, the sympathetics be divided on the one side, 
and the auricular branches upon the other, the ear vessels of the 
former side become widely dilated, and those of the latter markedly 
constricted. Under these conditions, if both ears be subjected to the 
action of water warmed to 54° C., there is a characteristic difference in 
their reaction. In the organ deprived of sympathetic influence the INFLAMMA TION 
congestion and hyperemia become yet more pronounced: an acute 
inflammation sets in which proceeds rapidly to recovery. In the 
opposite ear, with its constricted vessels, no hypersemia is set up; 
but there is stasis, and gangrene may supervene. These results have 
been confirmed by Roger, who, taking a rabbit and dividing the 
sympathetic on one side and then inoculating both ears with like 
quantities of a culture of the streptococcus of erysipelas, found that the 
erysipelatous process manifested itself much more promptly upon the 
paralysed side, and came to an end at an earlier date. The reverse was 
the case when the auriculars of the one side had been divided: here the 
process was of slower development than on the intact side, and of slower 
course, resulting in mutilation of the organ.1 
The inference to be drawn from these observations is that section of 
all the nerves passing to the rabbit’s ear permits the inflammatory process 
to run a more rapid course; section of the sympathetics (vaso-constrictors) 
alone has the same effect; while the uncontrolled action of the sym- 
pathetics after section of the auriculars (vaso-dilators) hinders or prevents 
the manifestation of the ordinary processes of inflammation, and by 
preventing the destruction or removal of irritant matter favours necrosis 
of the tissues. We have yet to learn whether these results are capable 
of a general application, and to discover how far they are borne 
out by clinical observations on diverse cases of localised paralysis. So 
far as they go they afford direct evidence of the power of the central 
nervous system to modify the course of the inflammatory process, while 
they demonstrate admirably how potent an auxiliary is the dilation of 
the vessels in the inflammatory process. 
Other evidence that the state of the nerve-supply of a region influences 
the manifestation of inflammation is afforded in sundry neuropathies. 
In all of these, in the present state of our knowledge, it is difficult to 
trace out the nervous factors associated with the lesions to which 
I refer. Our knowledge of the respective influences of trophic and 
vaso-motor nerves is far too limited to permit us to say more than 
that a relation exists between the condition of the nerve-supply 
of the affected area and the inflammatory lesions there observable; 
that in a certain number of cases inflammation affecting the area sup- 
plied by one branch of a nerve may have associated with it definite 
inflammatory disturbances in the areas supplied by other branches of 
the same nerve, and that, similarly, when inflammation affects a viscus, 
inflammatory phenomena may be sympathetically developed in regions 
innervated from the same area in the brain or spinal cord. I have 
already given examples in support of the first statement: the familiar 
redness, swelling, heat and pain of the side of the face which may 
accompany toothache is an example in support of the second, while the 
condition of labial herpes in pneumonia is an evidence of the results of 
1 Although these results have been criticised by Samuel and other observers, upon re- 
viewing carefully the whole literature of the subject, I cannot hut think that the above 
paragraph represents the general trend of more recent work. 112 
SYSTEM OF MEDICINE 
the third. Another example is to be found in the acute nephritis, which 
at times rapidly follows the passage of a catheter, or the impaction of a 
stone in the urethra. It is not unlikely that many of these sympathetic 
inflammations are not direct, but secondary. Thus, the first noticeable 
symptom of catheter fever is suppression of the urine. Such suppression 
might be brought about either by reflex contraction of the renal 
arteries, or, contrariwise, by reflex great dilatation and congestion of the 
vessels of the kidneys. If it be caused by the former then the nephritis 
can only be regarded as secondary, and as due to the injury done to the 
organ by the stoppage of its blood-supply for some little time. 
From the multitude of the factors involved, these examples, taken 
separately, afford at most only a great probability that the nervous 
system can directly originate inflammatory changes. There is, however, 
the clearest proof that the nervous system does possess this power, and 
this is afforded by the results of certain observations upon hypnotic 
effects. There are persons susceptible to hypnotic suggestion, in 
whom the suggestion that a red-hot substance has been placed upon the 
hand will, in the course of a few minutes, lead to great reddening of the 
part supposed to have been burned, and this reddening may be followed 
by great local exudation and swelling —in fact, by all the symptoms 
of acute inflammation. Here then actual inflammatory reaction follows 
supposed injury. 
It is unnecessary to do more than point out the light that this 
intervention of the central nervous system throws upon the subject of 
counter-irritation, and upon the modifications of the course of inflamma- 
tions brought about by idiosyncracy of the individual. 
From what has been said in the preceding paragraphs, it follows 
that: 
1. Acute inflammation in all its stages may proceed regularly in the 
absence of all centrifugal nervous influences. 
2. The vessels of an injured area are capable of reacting apart from 
central influences; it may be either directly, or under the control of a 
peripheral system of nerve cells. 
3. The central nervous system is capable of modifying the process 
of inflammation. It would appear that when the vaso-dilators alone are 
called into action the successive stages of the process are accelerated. 
When the vaso-constrictors alone are acting the process is retarded. 
4. Centrifugal impulses alone, apart from any local injury, may 
originate a succession of phenomena of inflammation in a part. 
5. Hence, in all probability a nervous and central origin must be 
ascribed to some, at least, of the sympathetic inflammations seen to occur 
in areas supplied by the other branches of a nerve supplying a part 
primarily inflamed; and again in areas supplied from the same region of 
the brain or cord as the inflamed organ. INFLAMMA TION 
Chaptek 6. On the Part played by the Cells of the Tissues 
As a consequence of irritation two opposed processes may be mani- 
fested in the cells of the affected area, changes leading to impairment 
and death, and changes leading to overgrowth and proliferation; de- 
generation and regeneration. 
Either of these two processes may, it is true, be wholly wanting. 
In very acute suppurative disturbances, destruction of the tissue cells 
and the steps leading to destruction may be the only recognisable 
changes. Again, in the first stage of most injuries, whether of me- 
chanical, chemical or bacterial nature, degenerative changes are wont 
to take the lead. On the other hand, there are irritants so mild that 
little or no cell destruction results from their action; an extreme 
example of this category of inflammations is seen in those epithelial 
overgrowths commonly known as “ corns,” due, as Sir James Paget 
pointed out in his lectures, to intermittent pressure and irritation of 
moderate intensity.1 Other examples are to be found in the “ catarrhal ” 
inflammations, in which there is marked initial overgrowth and prolif- 
eration of the cells of mucous membrane; and in tuberculosis, again, in 
which characteristically the earliest effects upon the pre-existing cells, 
produced by the presence and growth of the tubercle bacilli, are those 
of enlargement and multiplication necrotic changes, as a rule, only 
appearing at a much later stage. Once more, in the later healing stages 
of injuries, cell proliferation may be in the field alone. Nevertheless, 
in a very great number, if not in the majority of inflammations, the 
two processes may be found occurring together destruction and 
degeneration being in evidence at the focus of irritation, and growth 
and proliferation towards the boundary zone, where the irritant is 
acting in a less concentrated form. 
Although the two processes are thus so frequently associated, it will be 
well, for the orderly review of our subject, to consider them separately. 
Degeneration of the Tissue Cells.—Death of the pre-existing cells 
as an immediate consequence of injury cannot be regarded as one of the 
phenomena of the inflammatory process. Immediate death of the cells 
may be a result of injury, and the disintegration of the dead cells may 
in itself lead the way to all the symptoms of inflammation. But cessation 
llt may very well be that this is not an extreme example. Neoplasms as a class, 
whether malignant or benign, not improbably develop as a consequence of some irritation 
having an intensity just sufficient to induce cell proliferation, and continued for a time 
sufficiently long to impress upon the cells of the affected tissues the habit of rapid multipli- 
cation. There is evidence both in animal and vegetable pathology favouring this rela- 
tionship between inflammation and neoplastic growth. 
The objection may be raised, with considerable force, that substances which lead to 
cell-proliferation are stimuli and not irritants, and that a line should be drawn between 
inflammation proper and overgrowth the result of irritation. I, for one, would willingly 
make this difference, but while it is easy to draw the line in certain well-marked ex- 
amples, in others, as I shall proceed to show, cellular proliferation is so essential a part 
of the whole inflammatory process that the division becomes impossible. 
VOL. I I SYSTEM OF MEDICINE 
of action is not reaction, nor is failure response, and throughout this 
article inflammation has been considered as the reaction following 
injury, and the response to it. Thus immediate death of tissue cells is 
resultant and not reactive, and may be eliminated from the category of 
the essential phenomena of inflammation. 
The same is to some extent true of cell degeneration, but not 
entirely. While it is impossible nowadays to accept Virchow’s old 
view, that inflammation is essentially a process characterised by 
increased nutritive changes in the cells of the tissues, it remains most 
probable that in very many cases irritation induces increased, even if 
perverted, activity of certain orders of cells. The proliferation, swelling, 
and more or less rapid degeneration of these cells cannot be wholly 
ascribed to the toxic influence of the irritant, but must in part be 
regarded as a result of over-stimulation and overwork. This is most 
noticeable in connection with catarrhal and parenchymatous inflam- 
mations. In parenchymatous nephritis, for example, such as that set 
up by cantharidin or septic infection, the cells especially affected 
are those whose functions are especially excretory ; and their degenera- 
tion would appear to be intimately related to the performance of their 
functions. Such degeneration, preceded or accompanied, as it so fre- 
quently is, by excessive proliferation, may truly be regarded as reactive, 
and not as wholly and primarily destructive. 
Of the degenerations which affect the tissue cells in inflammation 
(and often at the same time the leucocytes) there are many varieties; 
in fact, according to the nature of the irritant, one, or other, or all the 
degenerations affecting the tissues in different pathological conditions 
may manifest themselves, save, perhaps, simple atrophy and pigmental 
degeneration (as apart from pigmental infiltration). Most commonly 
recognised are cloudy and fatty changes, but mucoid and hydropic 
changes are far more frequent than is generally noted. Even so special- 
ised a change as amyloid degeneration has been observed occurring 
locally in chronic inflammations as, for example, in gummata; while 
in these same chronic lesions hyaline degeneration in the vessel walls 
is very often to be encountered. 
There is also to be seen in inflammatory disturbances of moderately 
acute type a further form of degeneration, which receives a passing 
mention in the text-books, it is true, but so far has not to my knowledge 
been duly treated as an entity; nor has its significance been fully grasped. 
This is what may be termed “ reversionary ” degeneration. It is to be 
seen affecting tissues, in which the individual components in the fully- 
formed state are not single cells, but cell complexes or compounds. Such 
compounds are the voluntary muscle and medullated nerve fibres, 
and, as Grawitz has pointed out, the fat cells of connective tissue.1 
These are formed by the fusion and united growth of several cells; 
11 here, and throughout this article, leave wholly out of account Grawitz’s “ slum- 
bering cell ” theory a theory incapable of actual proof, and at variance with the cell 
theory upon which is based the entire superstructure of modern biology. INFLAMMA TION 
and in inflammation, as under otlxer pathological conditions, the de- 
generation of the cell-compound as a whole manifests itself by a certain 
amount of proliferation of the nuclei (of the muscle fibre, sheaths of 
Schwann, and periphery of the fat cells respectively), protoplasm can be 
observed to accumulate around these active nuclei, and with the assump- 
tion by the component cells of an independent existence the degeneration 
may be said to be complete that is to say, beyond this point only the 
shell and debris of the original compound are left to be considered. 
All these degenerations are inevitably associated with disturbance 
of the functions of the affected cells, and lead to their death if the 
irritation which has induced them be continued. But death is not the 
final stage to be considered. The ultimate fate of the necrosed cells 
varies according to the situation of the inflamed area, the intensity of 
the irritation, and the specific character of the irritant. From a free 
surface the dead material may be freely cast off. In acute suppurative 
inflammations, whether superficial or deep, and, in general, wherever 
there is an abundant determination of leucocytes, there obtains a diges- 
tion and solution of the necrosed cells; and, as I have already pointed 
out, this is associated with the development of peptones and albumoses, 
and is brought about largely through the extracellular action of the 
leucocytes. When there is a large area of cell destruction, with well- 
developed encystment and limitation of necrosis by granulation tissue, 
there the solution of the dead material and subsequent absorption may 
be incomplete, and a fatty debris left behind, which may eventually 
become infiltrated with lime salts (the calcareous degeneration falsely 
so-called). In tuberculosis, despite the presence of many leucocytes in 
the immediate vicinity, the dead material of the centre of the tubercle 
undergoes very little absorption, but remains as an inspissated, cheesy 
mass. In syphilis, on the other hand, in large gummata, while there 
is similar death of the central cells and absence of removal, fatty 
metamorphosis does not occur nearly to the same extent. 
Lastly, although very little is known about the subject, attention 
must be drawn to the fact that along with the tissue cells the inter- 
cellular matrix undergoes modifications or degenerative changes dur- 
ing inflammation. Among these, in all probability, is to be classed an 
increase in the amount of intercellular mucin, a mucoid degeneration. 
The inflammatory exudate is in many cases rich in mucin, and although 
our knowledge of the changes in the matrix is scanty, the fact that the 
tissue cells in general show little evidence of storage of mucoid or 
mucinogenous material, renders it probable that what mucin is formed 
is either excreted or elaborated between the cells. Connective tissue 
fibrils, which may be regarded as part of the matrix, undergo dissocia- 
tion and swelling, and eventually, in acute inflammation, disappear. 
In chronic disturbances they are especially prone to hyaline change. 
Regeneration of the Tissue Cells; Overgrowth and Proliferation. —ln 
the lower animals, as we know, injury and actual removal even of a large 
portion of the body may be followed by the complete reproduction of SYSTEM OF MEDICINE 
the lost part. In man, however, this reproduction of lost tissue is 
reduced to its lowest point; the higher the tissue the less, and the 
less perfect, the reproduction. Speaking generally, the tissues which 
show the greatest potentiality for reproduction are the least highly 
organised those composed of similar units. The “connective tissue” 
the lowest and most widely distributed retains the largest powers 
of proliferation and hyperplasia. 
In ordinary inflammation hypertrophy and hyperplasia of the con- 
nective tissue cells are absent at the focus of irritation. Here degen- 
eration is predominant. It is in the peripheral zone, away from the 
maximum concentration of the irritant, that (as shown in case after case 
of Leber’s long series of studies upon injury to the cornea), the con- 
nective tissue cells show signs of enlargement and proliferation, that 
they become more swollen and prominent, send out large processes, and 
may exhibit signs of active mitosis. It may be urged that this peri- 
pheral change is not inflammatory, but associated; yet, as I have already 
hinted, the signs of cellular regeneration may manifest themselves at so 
early a stage that it is impossible to disconnect them from the process 
of inflammation. This fact has been brought out with emphasis in 
Ranvier’s interesting series of studies on irritation of the peritoneum by 
weak solutions of caustic substances. If a few drops of aO3 per cent 
solution of silver nitrate be injected into the abdominal cavity of a rab- 
bit or guinea-pig an inflammation is set up which lasts for some days. 
At the end of twenty-four hours the portions of the serous coat of the 
abdominal contents which have been most affected are found denuded of 
their endothelium the cells have died and disappeared; but in other 
regions, less strongly affected, the endothelial cells present the reverse 
condition of overgrowth; their nuclei are swollen; the protoplasm, 
instead of forming a flattened plate, is swollen, and presents stellate pro- 
longations anastomosing with those of neighbouring cells. The under- 
lying vessels at this period show abundant evidence of inflammation; 
they are congested, and leucocytes are being poured out into the mesen- 
teric network. Within forty-eight hours there follows upon the inflam- 
matory exudation a rich development of fine filaments of fibrin, and along 
sundry of these filaments the enlarged endothelial cells send processes. 
Some of the cells become enormous, 100 /x or more in diameter. In this 
extension of the cells along the fibrinous framework we have probably 
the commencing formation of organised adhesions. The endothelial cells 
at this stage have become so modified from their previous quiescent flat- 
tened state that even outside the body they exhibit amoeboid movements. 
Up to this time no signs of nuclear division manifest themselves. 
According to Toupet, working under Gornil, it is not until the fourth day 
that mitosis is recognisable in this form of inflammation. But while 
inflammatory congestion, exudation of fluid, and diapedesis of leucocytes 
is proceeding actively, the modified endothelial cells of the regions that 
have not undergone the severest injury are with equal activity engaged 
in what it is difficult to regard as other than a reparatory process. INFLAMMA TION 
117 
As Baumgarten showed in his studies upon the development of 
tubercles, in the irritation set up by the growth of the B. tuberculosis in 
the tissue, a like overgrowth with proliferation of the fixed cells occurs 
in the immediate neighbourhood of the bacilli without any primary evi- 
dence of cell degeneration. It is true that of late the researches of Borel 
have thrown doubt upon Baumgarten’s observations, but they confirm 
the earlier researches so far as regards the mitosis of pre-existing cells, 
and the absence of degeneration of these in the earlier stages of the 
tubercular growth. Borel would regard all the large epithelioid cells 
of the tubercle as modified leucocytes. For myself I cannot admit that 
he has proved this, careful as his researches seem to be; and until the 
leucocytic nature of these cells be firmly established I am inclined, 
with the majority of histologists, to regard many of them as similar in 
nature and origin to the modified cells just described in connection with 
simple inflammation. 
The difficulty of determining the origin of the growing cells in 
inflammation has formed the greatest trial of the pathologist throughout 
an entire generation, and yet longer; nor can we now assert without 
chance of dispute what cells are mainly concerned in the formation of 
new tissue. 
When we examine newly-formed granulation tissue we can distin- 
guish cells of more than one type (1) small round cells with polylobu- 
lar and fragmented nuclei, (2) other cells containing oxyphil granules, (3) 
larger cells with a single nucleus and a relatively large quantity of proto- 
plasm, and again (4) cells of varying but generally large size, varying in 
shape, but on the whole having the appearance of spindle cells with single 
oval nucleus and abundant protoplasm. These can be made out easily. 
The first two forms of cells are clearly leucocytes. Further study of 
their fate shows that they disappear; they play no further part in the 
organisation of the tissue save that, as is well shown by Scheltema axxd 
Nikiforoff, many of them are absorbed by the growing connective tissue 
cells, and thus would seem to aid in their nutrition. The last form 
likewise presents, as such, no difficulties. These are fibroblasts cells 
in the process of growth into connective tissue. But what is their rela- 
tionship to the previous form, to the round mononucleated cells with 
fairly abundant protoplasm, what are these last, and what in short 
is the origin of the fibroblasts, —is it from leucocytes or from pre- 
existing connective tissue cells ? Upon this most difficult question 
more ingenuity and more research have been expended than upon any 
other part of this well-worked field of inflammation. 
There can be no doubt nowadays that a large proportion of the fibro- 
blasts in granulation tissue are developed from pre-existing connective 
tissue cells. The general consensus of recent researches leads de- 
cidedly in this direction; and it is from the laboratory of Ziegler, who 
by his classical observations led pathologists for some years to hold the 
contrary view, that the studies have emanated which most conclusively 
show the part played by the connective tissue; the researches of Kraift, SYSTEM OF MEDICINE 
Podwyssozki, Coen, Fischer, and Nik if or off, confirmed and strengthened 
by the researches of Arnold, Marchand, ifeinke, and Sherrington, all 
bring forward evidence in one direction. It is the clearly recognisable 
pre-existing cells of the tissue connective, endothelial and epithelial 
which show most constantly the signs of nuclear division: every 
stage of enlargement, mitosis and cell division, can be made out in 
them. Even if we did not possess the information afforded by nuclear 
changes, the fact that new tissue is always developed in the immediate 
neighbourhood of pre-existing tissue would in itself point strongly to 
this same conclusion. 
We may rest assured of this much. But can we advance farther, 
and state that all newly-formed connective tissue cells originate from 
the pre-existing cells of the tissue, and that none of them are derived 
from wandering cells ? In the present state of our knowledge the 
answer to this question must be an unhesitating “ No.” If we base 
our observations upon the morphology of the cells in granulation tissue, 
we find that with our present methods the large, round, mononuclear 
cells seen therein are undistinguishable on the one hand from large 
hyaline leucocytes, on the other from one stage in the development of 
fibroblasts. If we examine into their properties we find that they act 
as phagocytes incorporating the multinuclear leucocytes. The fibro- 
blasts, according to Nikiforoff’s careful studies, have an identical action; 
so also, according to Metschnikoff, Buffer, Borel, and others, have the 
large mononuclear hyaline leucocytes. If we study their mode of divi- 
sion they, like the connective tissue cells, exhibit indirect or nuclear 
division. It may be (as has been more than once suggested) that the 
large mononuclear hyaline leucocytes differ from the other forms in 
being of endothelial origin. Were this so a path would be found out of 
our present difficulty. Certainly the most that can now be said is that it 
is quite possible that among the higher animals this one form of wan- 
dering cell may be contributory to new fibrous tissue formation, quite 
possible that the connective tissue cells which develop as a result of in- 
flammation are not all derived from the pre-existing cells of the region.l 
It must be borne in mind that leucocytes, endothelial, and connective 
tissue cells are very simple forms of tissue, that they are all of like 
mesoblastic origin, and thus being homogeneous, may be more variously 
modified, without impairment of activity, than more highly specialised 
cells. I must here add that in lower forms —in the tadpole’s tail, 
for example Metschnikoff has followed day by day the transition from 
leucocyte into typical connective tissue cell, and that, largely in conse- 
quence of these observations, French pathologists hold the view that the 
leucocytes enter far more actively into new tissue formation than I here 
recognise. The German school, with the exception of Arnold (whose 
1 In this connection may be mentioned the observations of Metschnikoff, confirmed 
by Barfurth, and more recently by Dr. Joseph Griffiths, which show that in the degener- 
ation and disintegration of muscle fibres (of the tadpole’s tail) the proliferated nuclei of 
the fibres become the nuclei of individual wandering cells leucocytes. INFLAMMA TION 
119 
views correspond on the whole with my own), has with Ziegler passed 
over to the opposite camp of connective tissue only from connective 
tissue. For myself I have carefully sifted the evidence adduced by 
either side. What is said above gives, I believe, the estimate of the 
matter for the time being; while what follows gives in brief the state 
of our knowledge of the part played in inilammation by the tissue cells 
in general. 
(1) Two series of changes may occur in the cells of an inflamed tissue, 
which may be included under the terms degeneration and regeneration 
respectively. 
(2) The extent to which one or other of these series of changes pre- 
dominates varies with the nature and intensity of the irritant. 
(3) Degeneration and death of the tissue cells may be a direct and 
immediate result of the presence of the irritant, and then can scarcely 
be regarded as essential phenomena of inflammation. Or they may be 
of more gradual onset, associated with evidence of over-stimulation and 
increased activity of the cells. 
(4) Fatty, cloudy, hydropic and mucoid are the most frequent forms 
of degeneration affecting the tissue cells in acute inflammation; hyaline 
in chronic; other forms are rare. 
(5) The ultimate fate of the necrosed cells varies as the situation, 
intensity of irritant, and specific character of irritant. 
(6) Cell-proliferation is so constant an accompaniment of certain 
forms of inflammation that it is impossible to regard this as an adjunct 
and not as an essential part of the process. 
(7) The tissues which show the greatest potentiality for reproduc- 
tion in consequence of inflammation are those which are least highly 
organised. 
(8) The origin of fibroblasts and new connective tissue cells cannot 
be regarded as entirely determined, but this much would seem to be 
clearly demonstrated: (a) That a large proportion of the fibroblasts are 
derived from pre-existing connective tissue cells. (3) That in lower 
forms —■ as, for example, the tadpole leucocytes can be seen to develop 
into connective tissue cells, (y) It is quite possible, indeed probable, 
that in the higher animals one form of wandering cell, the large hyaline 
mononuclear, contributes to the formation of new fibrous tissue. 
Chapter 7. —On Fibrous Hyperplasia and its Relationship to 
Inflammation 
The succession of changes from embryonic cells to fully-formed tis- 
sue can best be studied in cases where there has been a relatively large 
area of destruction as, for example, after severe burns, or excision of 
organs or large portions of organs; or again, where inflammation has 
been of a chronic character. 
If healthy granulation tissue be examined, the process of growth is 
seen to originate in the immediate neighbourhood of if not in direct 120 
SYSTEM OF MEDICINE 
connection with the dilated new capillaries. It is around these vessels, 
formed of little more than a single layer of cells, that the fusiform fibro- 
blasts are in greatest abundance. At a later stage, in regions more remote 
from the advancing margin of the granulations, the fibroblasts have a more 
general distribution in the intercapillary spaces, and are more elongated; 
around them may be seen the earliest wavy fibres of white connective 
tissue. These are essentially of cellular origin —as much so as is the 
substance of striated muscle fibres. The elongated fibroblasts not only 
break or extend at their poles into fine processes, but also along their 
sides the protoplasm undergoes modification into fine parallel fibrillae. 
With the continuance of this change the cells become smaller and 
smaller until little is left but the attenuated nuclei, often so flattened 
and narrow as to be scarcely recognisable. It is generally accepted 
that the fibrillar substance contracts with increasing age; certainly the 
newly-formed cicatricial tissue diminishes greatly in volume, and with 
this diminution the previous great vascularity of the part disappears; the 
capillaries shrink until the majority become completely occluded. Thus 
in place of the abundant, soft and succulent granulation tissue, rich in 
cells, blood-vessels and exuded fluid, there is eventually a firm, shrunken, 
anaemic mass of fibrous tissue, with rare flattened nuclei, rich only in 
closely-pressed bundles of white, semi-transparent fibrils. 
Fibrous hyperplasia is to be encountered in almost every tissue of 
the body as a sequence of very diverse morbid conditions. To speak of 
it in any case as “ fibroid degeneration ”is a misnomer. The overgrowth 
of any tissue, however lowly, is not a degeneration. Fibrous tissue may 
and often does become the seat of degenerative processes, notably the 
hyaline; but that is another matter. To regard every condition of 
generalised or localised fibroid change of the organs of the body as a 
chronic “ —itis ”is equally erroneous, until we have proof absolute that 
connective tissue only undergoes excessive growth directly or indirectly 
under the stimulus of injury. It is interesting to note the opposed 
tendencies of the two branches of our profession on this subject; 
the surgeons strive to restrict the idea of inflammation to acute pyogenic 
disturbance, the physicians to extend the idea so as to include all 
cases of chronic progressive “ fibrosis.” I will not say that the latter 
is as untenable a position as the former, for it is a matter of peculiar 
difficulty and delicacy to state what is and what is not an inflamma- 
tory fibrosis; after all, there is more danger of being tossed about 
helplessly in the Charybdis of including too little, than there is of 
striking upon the Scylla of including too much in our idea of inflam- 
mation. 
Here I wish to point out how divergent are the conditions which 
lead to fibroid hyperplasia, and to draw attention to the fact that there 
is reasonable ground for not classing all forms under the one common 
heading, even though the resulting appearances may be undistinguish- 
able and the effects the same. 
Cicatricial fibrosis presents little difficulty; it is plainly the result of INFLAMMA TION 
121 
inflammation; so too is the fibrous overgrowth upon chronically inflamed 
serous surfaces. Capsular fibrosis is clearly of the same nature; it is 
to be seen around foreign bodies, around chronic abscesses, in the 
walls of tubercular cavities, and encapsulating tubercles, gummata, and 
other neoplasms inflammatory and non-inflammatory. Allied to these 
is the fibroid replacement in old infarcts (including that following 
upon “ myomalacia ” cordis). Here, studying a series of cases, it can be 
made out that the necrosed material becomes surrounded by a zone 
of inflammation, and that, with the passage of leucocytes into the 
dead area and absorption of the effete material, there is soon manifest 
a new connective tissue overgrowth advancing inwards from the peri- 
phery. 
Among the generalised scleroses there is one form frequently encoun- 
tered which may, without hesitation, be regarded as the accompaniment 
of inflammation. This is seen well in the general interstitial nephritis 
accompanying subacute and chronic parenchymatous inflammation of the 
kidney. Of similar nature are some forms at least of hepatic cirrhosis, 
diffuse syphilitic cirrhosis, the diffuse tubercular cirrhosis to which at- 
tention has more especially been drawn by French pathologists, and an 
extensive pericellular cirrhosis in cattle, which I have of late been 
engaged in studying, due, it would seem, to the abundant multiplication 
of a diplobacillus in the bile capillaries and liver substance. Whatever 
be the immediate cause of other forms of cirrhosis, overgrowths of fibrous 
tissue would appear in these to precede atrophy of the liver cells, and 
to be associated with the presence of an irritant. 
But there are other varieties of fibroid growth concerning which it 
is less easy to arrive at a just conclusion. First may be mentioned the 
replacement or compensatory fibroses. An excellent example of this is 
to be seen in the sclerosis of well-defined tracts of the spinal cord follow- 
ing destruction of the ganglion cells governing those tracts, or sections 
of the fibres, at a point proximal to their trophic cells. 
The fibrosis in these cases is not secondary to a progressive inflam- 
mation, but to a simple atrophy of the nerve fibres. These shrink, and 
their place is taken by fibrous tissue. Another equally instructive 
example is to be found in the dystrophic sclerosis of the cardiac 
muscle fibres to which attention has been called, more especially by 
Drs. Martin and Huchard. This occurs in certain cases of arterio- 
sclerosis, and is best seen in the papillary muscles, the fibroid change 
occurring, not around the thickened arterioles, but at the periphery of 
the area supplied by each. The muscle fibres around the arterioles are 
healthy; but farther away, through lack of nutrition, they have atro- 
phied, and their place is taken by a zone of fibrous tissue which fre- 
quently manifests hyaline degeneration. In this instance the morbid 
condition of the arteries is in itself a hindrance to active dilatation of 
the vessels, and the exhibition of the ordinary accompaniments of in- 
flammation. Indeed this peripheral zone is singularly free from leu- 
cocytes, yet well-marked sclerosis appears nevertheless. 122 
SYSTEM OF MEDICINE 
Can these be regarded as cases of inflammatory fibrous hyperplasia ? 
According to our definition they may: the fibrosis ensues as a reaction to 
injury. It is legitimate to conceive that the dying and atrophic tissue 
elements here, as in the grosser condition of infarct, act as irritants. 
But, on the other hand, the only recognisable evidence of inflamma- 
tion is this very extension of cicatricial tissue; and even this is strictly 
limited in amount, being just sufficient to replace the dead tissue, and 
nothing more. 
Active hyperaemia is not a prominent characteristic of any stage in 
the first instance cited above, and is throughout absent in the second. 
Still, as I showed in an earlier portion of this article when treating 
of injuries to non-vascular areas, active hypersemia is not absolutely 
indispensable. 
Active hyperaemia is entirely wanting in yet another form of fibrosis 
that resulting from passive congestion, whether of the blood (as in 
clubbed fingers, in that variety of cirrhosis of the liver which may 
result from obstructive lung or heart disease, and in the spleen of 
portal obstruction), or of the lymph (as in chronic oedema, sclerema, 
elephantiasis and macroglossia). Is this to be regarded as an inflam- 
matory fibrosis ? Everything points to the conclusion that connective 
tissue cells and their progenitors, like the Chinaman and the Polish Jew, 
can thrive and multiply upon a pabulum which is starvation to those 
of a higher standard. In passive congestion, as in obstruction to 
the onward flow of lymph, there results undoubtedly a bathing 
of the tissues with increased lymph. Can this alone account for the 
hyperplasia, or must we invoke the aid of the irritation or stimulus 
of- retained effete matters contained in the lymph? This question is 
one that is most difficult to answer. Underlying it are the further ques- 
tions whether one broad explanation can be found to apply to all cases 
of tissue hyperplasia; and whether cell growth in general, under physio- 
logical as under pathological conditions, is due to increased nutrition, or 
to stimulation of the cells, to increased physiological activity of the 
same, or to removal of pressure and other conditions preventing growth, 
or to a combination of all, or nearly all of these. This last question at 
present remains unanswered. In the examples before us of hyperplasia 
following passive congestion, one possible factor, that of removal of 
pressure from the cells, is absent; and we are narrowed down, I think, 
to two of the possible factors named above relatively increased nu- 
trition, and stimulation by effete matters. If it were shown that there 
are states in which stimulation or irritation by effete matters plays no 
part in the overgrowth of new connective tissue, then we could, I think, 
safely declare that forms of fibrous hyperplasia exist which cannot coma 
under the heading of inflammatory fibrosis, and that the fibrosis ol 
passive congestion may be included among them. 
Now such conditions do exist. That increased nutrition alone can lead 
to hypertrophy of the tissues was established long ago by Hunter’s classi- 
cal experiment of transplanting the cock’s spur on to the cock’s comb, —> INFLAMMA TION 
123 
moving it from a slightly vascular to a richly vascular region. In the 
ensuing overgrowth there can here be no question of irritation by any- 
thing beyond the normal blood.1 And passing from the general to the 
particular, we have evidence that there is such a condition as fibrous 
hyperplasia due, as it would seem, to increased nutrition unassociated 
with the presence of toxins or other cellular irritants. In his wonder- 
fully painstaking series of observations upon arterial changes, Thomas 
has adduced two cases which he describes, no doubt, as examples 
of endarteritis, but in which the inflammation is not apparent, 
nor indeed any factor other than altered tension of the arterial 
walls leading to altered conditions of nutrition. He shows that 
immediately after birth there is developed a thickening of the intima 
—a connective tissue proliferation immediately below the endothelium 
—of that portion of the aorta lying between the ductus Botalli and 
the passing off of the umbilical arteries. During later foetal life the 
umbilical arteries are the largest branches of the aorta; and, when the 
circulation through them is arrested, the aorta above is too large for 
the amount of blood requisite for the abdominal viscera and the lower 
extremities. The arterial current becomes therefore relatively slowed, 
and presumably, judging by the analogy of what occurs in the adult 
when large branches of the aorta are ligatured, the aortic blood pressure 
is for a time raised. With this slowing and increased pressure there 
appears a compensatory overgrowth of the intima leading to contrac- 
tion of the vessel and its lumen. Generally speaking, when the area 
of distribution of an artery is diminished, as, for example, when 
a limb is amputated, the artery shows a similar proliferation of the 
intima. In both cases the blood remains healthy, and the intima 
has undergone no injury; the only recognisable change has been a 
slowing of the blood stream, and probably increased blood pressure; 
and as the intima is nourished, not through the vasa vasorum, but 
directly from the main arterial fluid, it would appear that with the 
slowing an increased nutrition is brought into action. I can see no satis- 
factory reason for calling either of these cases an endarteritis. It is quite 
possible that other cases of thickening of the intima are due not to irrita- 
tion, but to increased nutrition brought about by heightened arterial 
tension. The difficulty urged by Councilman that high arterial pressure 
does not invariably lead to overgrowth of the intima is not, in my 
opinion, insuperable. It must suffice if here I point out that it is more 
than probable that certain cases of endarteritis are in no sense of inflam- 
matory origin, or secondary to degenerative changes; but are primarily 
associated with nutritional changes. In this connection it was shown 
by Prof. Roy and myself that when the aorta of the dog is suddenly 
and greatly constricted, and as a consequence the pressure in the 
11 here leave out of account a factor which may he important, but about which we 
know practically nothing namely, the effect of altered innervation. I am forced to 
assume, perhaps wrongfully, that, as this factor plays a like part in all the cases under 
consideration, it may for present purposes be disregarded. 124 
SYSTEM OF MEDICINE 
proximal portion of the vessel greatly increased; the plasma of the 
blood is forced into the cusps of the aortic valves, and vesicles of lymph 
make their appearance on the under surface in that region where fibroid 
thickening is most frequent in cases of chronic high arterial pressure. 
Thus, to express briefly the distinction that I would draw between 
inflammatory and non-inflammatory fibrous hyperplasia, I would say that 
where local injury leads to increased nutrition of the connective tissue, 
with increased functional activity of the cells, the ensuing fibrous hyper- 
plasia is to be regarded as of inflammatory origin; where, on the other 
hand, local injury is not recognisable as the primary cause of the cell 
growth, the hyperplasia must be held to be non-inflammatory. In pas- 
sive congestion, obstructed lymph-flow, and increased nutrition conse- 
quent upon arterial change, as in the cases cited above, we can so far 
see no cause for the fibrous hyperplasia beyond altered conditions of 
nutrition; there has been no primary lesion in the affected regions induc- 
ing the reaction. Such cases must be considered as non-inflammatory. 
But while I lay down this distinction, I must impress upon the 
reader that the last word has by no means been said upon this matter, 
and that further research may cause a radical reconstruction of our 
opinions. 
Forms op Fibrous Hyperplasia 
A. Of Inflammatory Origin. 
f 1. Cicatricial. 
2. Perivisceral. 
Localised 3- Capsular. 
4. Replacement 
Gross (of infarcts, etc.) 
1 Fine (dvstronhic sclern< 
Fine (dystrophic sclerosis, etc.). 
[5. Cirrhotic, associated with parenchymatous 
Generalised -f inflammation, interstitial and lymphan- 
L gitic. 
B. Of Non-Inflammatory Origin. 
1. Hyperplasia of increased (arterial) nutrition. 
2. ” of venous congestion. 
3. ” of lymphatic obstruction. 
C. Neoplastic. 
1. Fibromata. 
Upon the Increased Temperature of Inflamed Areas 
Very little has of late been added to our knowledge in this division 
of our subject: what is to be said appears now to be so well established 
that I need do little more than state the main conclusions. The long 
controversy that raged before these conclusions were fully accepted, and INFLAMMA TION 
125 
John Hunter’s original views shown to be in the main correct, scarcely 
comes within the scope of this article. 
1. The temperature of superficial regions is raised, it may be several 
degrees above the normal, by the onset of inflammatory hypersemia. 
2. The temperature of internal organs when inflamed may be raised 
above the normal, but undergoes no material increase beyond that of 
other unaffected internal organs tested at the same time. 
3. The rise above the normal, which is often present, is an indication 
of the febrile state accompanying the inflammation, and not of locally 
increased heat production. 
4. The increased temperature of superficial areas when inflamed is 
due, not to the production of heat in the part, but to the increased 
quantity of blood passing through it. When the congestion is so great 
that stasis ensues there may be actual decrease in the temperature of the 
part. 
5. The maintenance of high external temperature may exert a 
favourable effect upon the duration and progress of specific inflammation. 
Thus Filehne has recently shown that the course of experimental erysip- 
elas in rabbits is more rapid and more benign when they are kept at a 
high temperature than at a low. We possess no clear evidence that this 
is due to the unfavourable effect of the heightened temperature on the 
growth of the microbes. Pasteur’s well-known experiments upon the 
production of anthrax in fowls (ordinarily insusceptible to this disease) 
by lowering their temperature can be explained on other grounds. We 
have abundant evidence that heightened temperature promotes vascular 
dilation; the experiment of Pilehne may therefore supply a further 
demonstration of the favourable effects of dilation of the vessels and 
hypersemia in the inflammatory process. 
6. Low external temperature, or the application of cold to the surface, 
contracts the vessels : hence, upon the lines of what has already been 
said, it would appear that 
(a) It is calculated to diminish the amount of exudation. 
(b) It is calculated in consequence to diminish the pain associated 
with inflammation. 
(c) It has no directly good effect upon inflammation due to the 
presence and growth of pathogenetic micro-organisms, but 
may have the reverse effect of preventing the fullest reaction 
on the part of the organism. 
(d) Where the irritant does not itself grow and multiply, or present 
cumulative action, there the application of cold may not only 
be of no harm, but of positive advantage, by lessening the in- 
flammatory reaction and preventing this, where extensive, from 
being itself a cause of further injury to surrounding tissues. 
The increase of systemic heat will be considered in the article on 
Fever. 126 
SYSTEM OF MEDICINE 
PART 111. —On the Various Forms of Inflammation 
Chapter 1. Classification 
The minute changes which characterise the process as it affects one 
or other organ, and the various specific forms of inflammation, will be 
fully described in special articles. I have only to indicate more general 
causes and main varieties. To give a complete classification is impossi- 
ble unless each separate tissue be taken in order, for each tissue presents 
peculiarities either in liability to inflammation, or in the course assumed 
by the process. Even to attempt a classification in broad outline is 
beset with difficulties, for the inflammatory manifestation varies, not 
according to one or two series of causes, but according to four at least; 
the permutations are thus so numerous, and the appearances so varied, 
that to give an adequate scheme of classification would require a diagram 
in four dimensions. These four causes of variation are 
A. Nature of tissue affected. B. Position of tissue affected. C. In- 
tensity of irritation, or more correctly ratio between resistant powers of 
the organism and intensity of the irritant. 1). Nature of irritant. 
A. Nature of Tissue affected. —As I have already shown in the 
first portion of this article, there is in the earlier stages of the process 
a difference in the reaction of vascular and non-vascular tissues, the one 
series exhibiting marked congestion and vascular disturbance, the other 
not. At a later stage, or in more chronic irritation, as new vessels invade 
the non-vascular areas, the changes in the two series do no doubt approxi- 
mate ; but in the earlier stages we may distinguish between an ordinary 
inflammation and “ inflammatio sine inflammatione.” 
The relative denseness and compactness of the tissues also introduce 
characteristic alterations: a dense tissue, such as bone, does not show 
the signs of reaction to injury to nearly the same extent as does a loose 
tissue such as the omentum, for example thus, in the former there 
may be a process almost as atypical as in non-vascular areas. The rigid 
framework of a tissue like bone prevents great vascular dilatation and 
exudation, but at the same time may be the seat of great pain due to 
pressure of the confined exudate upon the nerve endings. The loose 
connective tissue of a structure like the omentum, on the other hand, 
permits great exudation with little or no pain. 
The influence of structure is well seen in comparing the course of in- 
flammation affecting cutaneous, mucous and serous surfaces respectively. 
Where we have to deal with cutaneous surfaces, or surfaces formed of 
squamous epithelium, there the increased exudation, and the resistance 
offered by the layers of flattened cells to the free exit of the exuded 
fluid, lead towards the formation of vesicles or blisters. In the case of 
serous surfaces, which form the walls of a moist cavity, the irritant, 
affecting primarily but one portion of the surface, is very likely to be 
borne into the cavity with the exudate and to set up an inflammation INFLAMMA TION 
127 
extending over a very large portion of the surface. Mucous and cuta- 
neous surfaces, which are not thus the boundaries of cavities, exhibit a 
more marked disposition to the production of localised inflammation and 
of ulcers; the superficial layers indeed of a well-formed epithelium or 
mucous membrane, by the protective powers of their cells, form a defence 
against irritation from without; thus the superficial exudate from a 
region of local inflammation cannot easily produce a superficial exten- 
sion of the process. 
Not only the nature of the tissues, but their function also, profoundly 
affect the character of the inflammatory manifestation. Thus, excretory 
organs, by the very nature of their function, during the attempt to 
remove noxious substances from the system, are especially liable to 
generalised parenchymatous inflammations, the irritation not being 
local, but affecting at the same time all the cells whose part it is to 
take up and excrete the irritant bodies. 
B. The Position of Tissues. —lt is difficult to consider the position 
and relationship of tissues as they affect the inflammatory manifesta- 
tions, without continually touching upon their structure. Nevertheless, 
the two, though very closely connected, do not go hand in hand. 
A familiar instance of modification in form brought about by position 
is to be seen in the result of suppurative inflammation in the develop- 
ment of ulcerous conditions when the process affects free surfaces, of 
abscesses when it attacks deeper tissues. The process in the two cases is 
virtually the same: there is the same abundant determination of leuco- 
cytes, the same degeneration of them into pus. Yet apart from the 
gross difference in form, there are minor differences between the two. 
There is, for instance, relatively much more serous exudation from the 
free surface of an ulcer than there is into and around an abscess. As 
a general rule, inflamed tissues near a free surface are the seat of more 
abundant exudation. Of this liability for free surfaces to be the seat 
of serous inflammation I have already spoken. The skin, with its thick 
dermal layer, affords a good example : when the full suppurative stage 
is not reached, inflammation affecting the outermost layers of the derma 
is most often of a vesicular or oedematous character; when it affects 
the deeper layers of the derma the serous infiltration is less evident. 
Yet another example of the influence of position in modifying form 
is seen in enteric fever. In this malady, the lymphoid tissue forming 
the Peyer’s patches becomes the seat of excessive cellular infiltration 
and proliferation, undergoes necrosis, and is cast off, leaving the well- 
known ulcers. The lymphoid tissue of the neighbouring mesenteric 
gland likewise undergoes great infiltration and enlargement, but necrosis 
rarely implicates the whole of a gland: notwithstanding the previous 
extensive inflammation, the glands commonly recover their normal 
appearance and size. 
Beyond this there are few broad principles to be laid down concern- 
ing the relationship between forms of inflammation and position that 
do not essentially depend upon the structure and functions of the tissues. 128 
SYSTEM OF MEDICINE 
Much can be said concerning the intimate connection between position 
and liability to inflammation; but this and the allied and most impor- 
tant subject of the protective mechanisms of sundry tissues against 
injury are away from our present point. 
C. The Relative Intensity of the Irritant is a more frequent and 
potent cause of variation. I have already in several places referred to 
the ratio between the resistant powers of cells and the intensity or 
virulence of the irritant as it affects the inflammatory process, and have 
shown how much that was previously vague has been made clear by 
bacteriological research; while, at the same time, it has brought home 
the truth that the various forms of inflammation merge insensibly one 
into the other. 
Broadly speaking, it may be stated, as a result of these studies, 
that, center is paribus, increased virulence of any given microbe or 
diminished power of resistance on the part of the organism or of the 
tissues, leads to corresponding alterations in the phenomena of inflam- 
mation at the region of inoculation; and vice versa. 
Thus, if a pathogenetic microbe, such as that of anthrax or erysipelas, 
be greatly attenuated, the effects of inoculation into the subcutaneous 
tissues may be scarcely recognisable. If the attenuation be not so extreme 
some hypersemia, a determination of leucocytes, and, relatively, very 
little exudation, will be seen; and in the course of a day or two all 
traces of inflammation may have disappeared. With slightly more 
virulent microbes the migration of leucocytes may be followed by their 
breaking down and consequent abscess formation; with further increase 
of intensity of action the migration of leucocytes may be wanting, 
while the exudation extends and the inflammation rapidly spreads and 
leads to a septicaemia. A like series of changes is observable if the 
strength of virus be constant and animals more and more susceptible 
(or less and less refractory) be inoculated. 
The variation in tubercular lesions, from isolated dense fibroid 
masses to loosely formed cell accumulations and diffuse tubercular in- 
flammation, is evidently explicable on this law. The law holds good 
also, not merely for bacterial products, but for other irritants also. The 
effect of croton oil varies with the strength of the solution applied; and, 
as shown by Samuel, according to the condition of the animal. The 
same is true of abrin and other vegetable extracts. 
Turning to physical irritants, while here the intensity of the irritant 
alone or almost alone is called into play, numerous examples can be 
given of the effects of variation in this one respect upon the inflamma- 
tory manifestation effects of cold, for instance, varying from chilblain 
through inflammatory oedema to gangrene; of heat varying from 
hypersemia through vesicular inflammation to complete destruction of 
tissue; and, again, effects of caustic substances. In this era of aseptic 
surgery we may forget what was well known to the last generation of 
surgeons, that caustic substances may be employed either to originate a 
benign and reparative inflammation (as in the case of indolent ulcers) ; INFLAMMA TION 
129 
or, in larger quantities or greater intensity, to bring about a state in 
which the death of the tissue elements is far in excess of the subsequent 
repair. Thus then, according to the above-mentioned ratio, inflamma- 
tion in a tissue may vary by insensible gradations from a mere hypermmia 
up to a spreading suppurative or gangrenous process ; and from a purely 
local manifestation to the development of what may be termed an in- 
flammation of the whole organism. 
D. The Nature of the Irritant. —lt is clear, then, that it is impos- 
sible to base a classification upon the nature of the irritant: the 
attempt to mark off sharply the inflammations caused by mechanical 
and chemical noxae from those produced by bacteria and their products 
must be given up. Hliter’s proposition that suppuration can only be 
induced by microbes has been repeatedly shown to be erroneous. 
Thanks more especially to the researches of Councilman, Leber, Grawitz 
and de Bary and Straus (many more names might be mentioned in this 
connection), we now know that many chemical substances are capable 
of causing pus formation.1 Among these may be mentioned turpen- 
tine, croton oil, mercury, copper and silver nitrate. On the other 
hand, although this pyogenetic property is not confined to microbes and 
their products, yet among microbes it is not the common property of all. 
Some, like the bacillus of tetanus, never in themselves induce pus forma- 
tion: others, like the bacillus of tuberculosis, lead characteristically to 
tissue growth and the formation of inflammatory neoplasms rather than 
to pus formation. Even among those which, like the micrococci, are 
highly pyogenetic, the formation of abscesses only occurs when there is 
a definite relationship between the virulence of the microbe and the 
resistance of the organism. The reverse is equally true, that numerous 
microbes, not specially pyogenetic, produce pus under peculiar condi- 
tions. Thus, the bacillus of enteric fever, when it multiplies in the 
middle ear, induces a suppurative otitis, and, as Dr. C. F. Martin has 
shown, it is further capable of originating a suppurative arthritis. 
In fact, under varying conditions the same microbe can induce very 
various forms of inflammation. Thus, Charrin has shown that the B, 
pyocyaneus and its products are capable of inducing in one organ the 
kidney pathological conditions so diverse as acute, chronic, parenchy- 
matous, interstitial and thrombotic nephritis, with, in addition, cyst 
formation and amyloid degeneration.2 This same microbe can induce 
acute suppuration in the anterior chamber of the eye ; and when inocu- 
lated into the blood cause a haemorrhagic inflammation of the serous 
surfaces. Hence we can proceed further and state that no strict classi- 
fication of inflammation can be made according to the nature of the 
1 While this is so, it must he borne in mind that under ordinary conditions these 
substances very rarely act upon the organism in a state of sufficient concentration to he 
pyogenic. Thus, while it is impossible to make a sharp line of demarcation between 
bacterial and chemical irritants, it holds true in the main for man that suppurative dis- 
ease is an indication of the presence and growth of microbes. 
2 These changes are comparable with the diverse conditions of the kidney in the 
human being brought about by the scarlatinal virus. 
VOL. I K 130 
SYSTEM OF MEDICINE 
bacterial irritants: it is, however, possible to make a general grouping 
of those affecting man, as follows : 
(i.) Micro-organisms characteristically leading to pxis and abscess 
formation Staphylococci and streptococcus pyogenes, B. anthracis. 
(ii.) Those leading to abundant exudation with necrosis —B. of 
malignant oedema. 
(iii.) Those leading to cellular infiltration without usually causing 
abscess formation B. typhi abdominalis, M. gonorrhoese, B. diphthe- 
ria, etc. 
(iv.) Those inducing characteristically the development of inflam- 
matory neoplasms —B. tuberculosis, B. pseudo-tuberculosis, B. mallei, 
Actinomyces, Aspergillus fumigatus. 
Similarly, chemical substances may roughly be grouped into 
(a) Substances causing so slight an irritation when introduced into 
the organism as to induce cellular overgrowth only in their immediate 
neighbourhood such as bland foreign bodies, bullets, etc.; inhaled 
particles of coal, stone, iron, and the like, conveyed into the pulmonary 
lymphatics. 
(b) Substances leading to vesicular inflammation, e.g. blistering 
agents, such as cantharides. (This result, however, depends more upon 
the position than the nature of irritant.) 
(c) Substances leading to cell necrosis, followed by the formation 
of granulation tissue caustic agents. 
(id) Substances leading to cell necrosis and suppuration, such as 
copper, mercury, mineral acids, etc. (a very rare result in man). 
These lists, from the considerations given above, are necessarily un- 
satisfactory and imperfect. 
Other Considerations. Among other factors varying the inflamma- 
tory process may be mentioned the duration of the action of the irri- 
tant, which of necessity must modify the extent of the manifestations 
of disturbance in the tissues. A simple aseptic incision, for example, 
leads to a much milder and slighter series of changes than do the 
prolonged presence and growth of the tubercle bacillus. Yet while at 
first it might appear an easy matter to name case after case where the 
irritant has but a momentary action, upon further consideration it is 
found that, in the majority of cases of purely mechanical injury, this 
is not the case; or, to express the matter more exactly, in the case of 
physical injuries, it is not the act of wounding that causes the inflam- 
mation, but the damage inflicted upon the cells of the tissues; as, to a 
very large extent, inflammation is set up by the products of the injured 
and destroyed cells. A bone may be suddenly broken, and neverthe- 
less, even under the most favourable circumstances, pain, swelling, and 
congestion may affect the region of fracture for several days. One or 
other region of the body may be rapidly frozen: the inflammation 
does not manifest itself till after the physical agent has ceased to act, 
but it continues for hours, and even for days. 
There are, moreover, physical irritants of another nature producing INFLAMMA TION 
131 
definitely chronic inflammation; I refer to foreign bodies which have 
gained an entrance into the system. These if bland in themselves may 
nevertheless cause irritation. A good example of the extensive inflam- 
mation which such bodies may set up is seen in the dense fibrous inter- 
stitial tubercular masses developed in the lungs of stone-masons around 
fine silicious particles carried into the lymphatics from the alveoli. 
From such examples it will be evident that no satisfactory distinc- 
tions between bacterial irritants on the one hand, and physical irritants 
on the other, can be founded on the duration of irritation. This factor 
plays no easily recognised part in determining the various forms of in- 
flammation, and consequently I have forborne to place it in the list at 
the beginning of this chapter. 
In thus passing rapidly over the influence of each of the four main 
causes of variation I have of necessity excluded sundry forms of in- 
flammation due to the combined action of two or more. There are, for 
instance, such well-marked forms as the catarrhal and croupous, due to 
the interaction of all four factors: embolic inflammation and lymphan- 
gitis have also been passed over; these, however, are not so much forms 
of inflammation as inflammatory processes occurring in special regions 
as a result of special methods of conveyance of the irritants. 
The factors then are so many, and their interaction so varied, that 
anything approaching to an orderly classification is hopeless. What I 
have here written must be regarded, not as an attempt to formulate 
such a classification, but as an attempt to indicate briefly how the nature 
and position of the tissues, and the nature and intensity of the irritant 
bring about modifications in the process of inflammation. 
Chapter 2. —Oh Systemic Changes Consequent upon 
Inflammation 
The results of an acute local inflammatory process are not confined to 
the immediate locality, but associated alterations in the system at large 
have long been recognised; yet while recognised these systemic changes 
have been but little studied: I cannot pass the matter over in silence, 
but my setting forth of it must necessarily be very brief and imperfect. 
I cannot here say more upon the effect of local irritation on the 
nervous system than that, apart from direct reflex action leading to 
changes of nervous origin in the region of injury and the reflexes 
affecting associated regions, the higher centres, and through them the 
system at large, may become affected by paths that it is not always 
easy to trace. 
The disturbances of the nervous system which accompany local injury 
can be but vaguely and indefinitely described. As regards the secondary 
effects, the recent most suggestive work of Prof. Roy and Dr. Cobbett 
upon Shock [vide art. on “ Shock ” in a later volume] indicates that there 
is here a rich field for yet further research. Of the changes in the general 
circulation, and more especially in the circulating blood, thanks to the 132 
SYSTEM OF MEDICINE 
observations of Yon Limbeck, Eleder, Lowitz, and Sherrington, we are 
in possession of more exact knowledge. On acute local inflammation 
of some extent the circulating blood becomes inspissated; by exudation 
it loses some of its plasma, while the more solid constituents the red 
corpuscles —do not escape. The amount of fluid lost to the circulation 
is not equalised by increased entrance of lymph into the circulation: in 
one experiment of Prof. Sherrington the blood remained apoplasmic (i.e. 
its specific gravity remained heightened) for more than sixty hours after 
the infliction of injury. This apoplasmia or diminution in the relative 
amount of plasma in the blood appears to depend in some measure upon 
the extent of the vascular area involved in the inflammation; for example, 
Sherrington shows that when both feet are involved, by plunging the limbs 
in water of 52° G., the apoplasmia is more severe than in experiments 
affecting one foot only. Another well-marked change in the blood concerns 
the leucocytes. As suspected by Lowitz and proved by Sherrington, there 
is, in some forms of inflammation at least, a primary diminution in the 
number of leucocytes per unit volume of blood (leucocytopenia), followed 
by a marked increase in the number of leucocytes in the blood (leuco- 
cytosis). The number of leucocytes was in some instances increased 
sevenfold. In the leucocytopenia of inflammation, the diminution is 
chiefly confined to the finely granular leucocytes the finely granular 
oxyphile cells of Ivanthack and Hardy. These observations of Sherring- 
ton are confirmed by the observations of Everard, Demoor, and Massart. 
Whether the diminution be due to disintegration, or to collection in 
some area of the circulation, is not yet determined. The leucocytosis 
may become obvious within an hour after the establishment of a local 
lesion; and it may be prolonged for several days, even in cases where 
the injury has been of a mechanical nature. Here, again, according to 
most observers, it is chiefly the polynuclear or finely granular oxyphile 
cells which increase in numbers. It is interesting to note that coinci- 
dently the coarsely granular eosinophile cells appear to undergo great 
diminution. I can do no more than point out the existence of those 
blood changes, and further that changes in the number of leucocytes in 
the blood are certainly not accounted for by the number passing from 
the blood into the inflamed area. It would seem that local inflamma- 
tion in some way brings about an over-stimulation of lymph glands, 
whereby an increased number of leucocytes are poured into the blood; 
or it may initiate increased proliferation of the leucocytes already in 
the circulation; but how one or other of these effects is produced is 
at present unknown. Certainly the direct introduction of the products 
of bacterial growth into the circulating blood may lead to a more or less 
pronounced and rapid diminution of the number of leucocytes in the 
blood, and this diminution, as shown by Lowitz, may be preliminary 
to a subsequent increase. 
The further important general disturbance associated with local 
injury, more especially when of bacterial origin, namely, the occurrence 
of fever, will be described in another article. Bacteriological studies INFLAMMA TION 
lead to tlie conclusion that traumatic fever, at any rate, is largely due to 
the diffusion in the blood stream of soluble bacterial products, and of the 
products of tissue destruction derived from the inflammatory focus. 
Chapter 3. Conclusion 
In studying thus the reactions of the organism to injury, we 
are impressed by the multifariousness of natural processes; the end 
may be attained not in one way only but in many. “It is not by 
cells of one order alone—by phagocytes —or by leucocytes in general 
and only leucocytes, or merely by the reaction on the part of the fixed 
cells of the tissue, or by vascular changes alone, or by altered tempera- 
ture, or solely by the chemical and mechanical action of the exudate that 
repair is effected. All means are employed to antagonise the irritant and 
to effect healing. The cells of the body, fixed and free, play their part; 
the nervous system aids the process; the bodily humours render efficient 
help; modifications in the vessel walls and blood stream are valuable 
auxiliaries. Diverse processes are employed, now one more particularly, 
now another, according to the needs of the moment, but none exclusively.” 
The time has come when, example after example having clearly indi- 
cated the meaning and the tendency of that response, we may securely 
acknowledge the tendency, and see in inflammation not merely the re- 
sponse to injury, but the attempt to repair injury. To object that a 
definition containing this statement is teleological is absurd in the face of 
fact after fact that can be interpreted on this assumption only. What is 
the development of cicatricial tissue but an attempt at repair ? What 
other meaning can be ascribed to the increased bactericidal power of the 
inflammatory exudate as compared with that of ordinary lymph and 
blood serum ? Why do leucocytes accumulate in a region of injury ? 
Why do some of them incorporate bacteria and irritant particles, and 
others bring about the destruction of these without necessarily ingest- 
ing them ? All these are means whereby irritants are antagonised or 
removed, and reparation and return to the normal sought after. 
It must be kept in mind that attempt.to repair may be far from 
repair. Indeed, we frequently find that the reaction to injury is dispro- 
portionate to the strength of the irritant, being either insufficient or ex- 
cessive. The exudation may possess but slight bactericidal powers, or 
may be poured out in such quantities that the microbic irritant, instead 
of being retained in the region of injury, is conveyed outside that region; 
the wandering cells instead of destroying, may undergo destruction; they 
may incorporate bacteria, but not be able to annihilate them; the fixed 
cells may either form an incomplete cicatrix, or continue to proliferate in 
excess. The means of defence on the part of the organism are not so 
much a preparation in advance as an inheritance or an acquirement 
either a transmission from those forms which, being possessed of the most 
highly developed means of defence, have survived while forms with fewer 
resources have been destroyed; or, on the other hand, an accession derived 134 
SYSTEM OF MEDICINE 
from previous successful resistance: not being a preparation in advance, the 
reaction to injury is not exactly proportionate to any and every irritant. 
But the mere statement that inflammation is an attempt to repair 
injury, or that it is the response thereto, is insufficient as a defini- 
tion, for thereby the general disturbances which may accompany the 
changes occurring at the seat of lesion are included; these, however, may 
be excluded without seriously affecting our conception of the process, in 
fact with positive advantage to a clear comprehension of the distinction 
between inflammation and fever. And, further, if what I have urged in 
the chapter upon the part played by the nervous system be correct, 
account must be taken of the fact that the leading phenomena associated 
with the inflammatory process may occasionally present themselves solely 
under the direction of perverted nerve action, and apart from actual local 
injury. 
Hence I am inclined to consider that we can now pass beyond the 
conception of the process with which I began this article, and cannot 
merely regard it as a succession of changes in a part constituting the re- 
action to injury, but can with propriety acknowledge the purpose of that 
succession. From these considerations lam led to define inflammation 
as the series of changes constituting the local manifestation of the attempt at 
repair of actual or referred injury to a part, or, briefly, as the local attempt 
at repair of actual or referred injury. 
So diverse are the opinions of pathologists upon many branches of 
this subject of inflammation, and so great is the amount of recent research 
that I can neither hope that all the conclusions here set down will gain 
acceptance, nor that in these pages, inevitably condensed as they are, I 
have succeeded in recognising and duly acknowledging all work of primary 
importance. It is possible also that, having been unavoidably prevented 
of late from seeing and discussing with others the results they have ob- 
tained, I may in some cases have viewed facts in a wrong perspective. 
In the rapid progress of our science, much, it may be, that is here set 
forth will be modified. Nevertheless I hold that the conception of the 
inflammatory process indicated in this article is that which embraces the 
largest number of like phenomena, and excludes most satisfactorily those 
which if associated are unessential; and that it is by the study of cellular 
pathology in its strictest sense that the surest advance has been and is 
to be made in our knowledge of this the dominating process in disease. 
John George Ad ami. 
SELECT BIBLIOGRAPHY 
I. Op Inflammation in General 
1. Bennet. On Inflammation. Edinburgh, 1844.—2. Billroth. Wiener Tdin. 
Wochenschr. 1892. Nos. 1 and 2. —3. Bouchard. Semaine med. 1891. No. 20. 
4. Burdon-Sanderson. Holmes’s System of Surgery, i. (gives extensive select bibliog- 
raphy).— 5. Burdon-Sanderson. Croonian Lectures, 1892. Vide Lancet, ii. 1892, 
pp. 1027, 1083, 1149, and 1207. —6. Cohnheim. Vorlesunqen, second edition. 
Leipzig, 1882. Translated by Dr. A. B. M‘Kee, New Sydenham Society, 1890. ■ INFLAMMA TION 
7. Cornil et Ranvier. Manuel d’Histologic pathologique, i.— 8. Councilman. 
Dennis’s System of Surgery, i. 1895.—9. Hamilton. Text-hook of Pathology, i. 
1889 (gives extensive bibliography). —lO. Huter. Grundriss der Chirurgie, i. 
1883. —ll. Koch. Wundinfectionskrankheiten. Leipzig, 1878.— 12. Leber. Die 
Entstehung der Entzundung. Leipzig, Engelmann, 1891. —l3. Lbtulle. L’lnflam- 
mation. Paris, 1893.—14. Metschnikoff. Pathologic compares de Vlnflammation. 
Paris, Masson, 1892. Eng. transl., London, 1894. —l5. Neumann. “ Über dem 
Entziindungsbegriff,” Ziegler’s Beitr. v. 1889, p. 347. —l6. Recklinghausen. 
Handhh. d. allgem. Path. 1883. —l7. Rosbr. Entzundung und Heilung. Leipzig, 
1886. —lB. Samuel. Virch. Arch. Iv. 1872, p. 380. —l9. Samuel. Die Entziind- 
ungsprocess, 1873. 20. Thoma. “Ueber Entziindung,” Berlin klin. Wochenschr., 
1886 (on the suppression of the term “ Inflammation ”). 21. Virchow. Cellular 
Pathology. Eng. transl. from second edition by Chance. London, 1860. 22. Wagner. 
Hdbuch. der allgem. Path. Eng. translation, New York, W. Wood, 1879 (gives older 
literature very fully). 23. Weiqert. “ Entziindung,” Eulenburg’s Bealencyclopddie, 
1880, iv. p. 644. 24. Ziegler. Lehrbuch der allgemeinen pathologische Anatomic. 
Bth German edition, 1894. 25. Ziegler. Rede gehalten am 25 April 1892 zur akademi- 
schen Eeier. Freihurg, Lehmann, 1892. 
11. The Comparative Pathology of Inflammation 
26. Greenwood, Miss M. —J. of Physiol, vii. 1886, p. 254; viii. 1887, p. 263; 
xi. 1890, p. 576; xvi. 1894, p. 441. 27. Proc. Roy. Soc. liv. 1893, p. 466, “Inter- 
cellular Digestion.”—2B. Hardy. J. of Physiol, xiii. 1892, p. 165, “Blood Corpuscles 
of Crustacea.” 29. Krukenberg. Enters, a. d. physiol. Inst, in Heidelberg, ii. 
1878, p. 273, “ Intercellular Digestion.” 30. Le Dantec. Ann. de I’lnst. Pasteur, iv. 
1890, p. 776, and v. 1891, p. 163. 31. Lobb. Biol. Lectures, Marine Biol. Lap., 
Wood’s Hole, 1893. Boston, Ginn and Co., 1894, p. 43. 32. Metschnikoff. A. de 
I’lnst. P. hi. 1889, and No. 14, gives main literature.—33. Pfeffer. Enters, a. d. 
botan. Inst, in Tubingen, vols. i. and ii. 34. Rbinke. Enters, a. d. bot. Inst, in 
Gottingen, 1881. 35. Stahl. Botan. Zeitung, 1884, Nos. 10-12. 
111. The Steps of the Inflammatory Process in the Higher Animals 
In addition to Nos. 6, 7, 8, 12, 19 and 23, consult 36. Flemming. Virch. Arch. 
Ivi. 1872, p. 146, on “Development of Fibrin in Inflamed Tissues.” 37. Hess. 
Virch. Arch. cix. 1887, p. 365. 38. Hohnpeldt. Ziegler’s Beitr. iii. 1888, p. 343. 
39. Jacobs. Beitr. z. Histol. d. acut. Entzundung d. Cornea, Inaug. Diss. Bonn, 
1887.—40. Ranvier. Ctes. rend. d. I’Acad. d. Sc. 1891, April 20th, p. 845. 41. 
Senftlebbn. Virch. Arch. Ixxii. p. 542. A satisfactory bibliography of this sub- 
ject is given by Burdon-Sandbrson, Nos. 4 and 5. For full references to recent work 
upon mycotic inflammation consult Baumgarten’s Jahresbericht. 
IV. On the Forms and Varieties of Leucocytes 
42. Ehrlich. “ Farbenanalytische Enters, z. Histol. u. Klinik des Blutes,” 
Gesamm. Mitthl. Berlin, Hirschwald, 1891.—43. Everard, Demoor, and Massart. 
A. de I’l. P. vii. 1893. 44. Glugb. Observat. nonn. microscop, in Inflamm. 1835.— 
45. Gulland. Lab. Rep. R. G. P. Edin. iii. 1891, p. 106.—46. Gulland. J. of 
Pathol, ii. 1894, p. 447. 47. Wharton Jones. Phil. Trans. 1846, p. 64. 48. 
Kanthack. Med. Chron. New series, i. 1894, pp. 246, 332. 49. Kanthack and 
Hardy. J. of Pathol, xvii. 1894, p. 81; and Phil. Trans. 1894. —6O. Mesnil. 
A. de VI. P. ix. 1895, May.—sl. Metschnikoff. B. M. J. 31st Jan. 1891, and 
No. 14. 52. Ranvier. “Des Clasmatocytes,” Ctes. rend. d. VAcad. des Sc. cx. 
1889, p. 165.—53. Rieder. Beitr. z. Eenntniss d. Leucocytose, Leipzig, 1892; and 
Atlas d. klin. Microscopie des Blutes. Leipzig, 1892. —54. Rindflbisch. Pathol. 
Histologic, 1861; und Exptelle. Studien ii. d. Histologic des Blutes, Leipzig, 1863.— 
55. Max Schultze. Arch. f. mikr. Anat. i. 1863, p. 1. —56. Sherrington. Proc. 
Roy. Soc. Iv. 1893, p. 161. —57. Siawcillo. A. de VI. P. ix. May 1895. —For fuller 
bibliography consult Nos. 46, 48, and 53. 136 
SYSTEM OF MEDICINE 
58. Borrel. A. de I’lnst. Pasteur, vii. 1893, p. 593.—59. Duenschmann. J. of 
Pathol, iii. 1894, p. 118.—60. Faber, Knud. J. of Pathol, i. 1893, p. 349.—61. 
Koch. Mittheil. a. d. kaiserl. Gesundheitsamt, ii. 1884. 62. Langhans. Virch. 
Arch. xlii. 1868, p. 382, and xlix. 1870, p. 66. 63. Marchand, P. Virch. Arch. 
xciii. 1883. 64. Johannes Muller. Ueher den feineren Bau und die Formen der 
Krankhaften-Geschwulste. Berlin, 1838.—65. Ribbert. Der untergang, pathogen. 
Schimmelpilze im Kbrper. Bonn, 1887.—66. Ruffer. A. de I’lnst. P. v. 1891. 
67. Soudake witch. Virch. Arch. cxv. 1889. 68. Stchastny. A. de I’lnst. P. 
v. 1891, p. 225. 69. Virchow. Virch. Arch, xiv. 1858, p. 47.—70. Wbigert. D. 
med. Wochenschr. 1885, and Virch. Arch, cxiii. 1889. 71. Ziegler. Expt. Unter- 
such. ii. d. Herkunft d. Tuberkelelemente. Wurzburg, 1875. Earlier literature given 
by Marchand (No. 63), later by Faber (No. 60). 
V. On the Nature of Giant Cells 
VI. On Chemiotaxis 
72. Councilman. Virch. Arch. xcii. 1883. 73. Gabritchbwski. A. de I’l. P. 
iv. 1890, p. 346.—74. Kanthack. See No. 48, and B. M. J., June 18tb, 1892. 75. 
Leber. See No. 12. 76. Massart, J. A. de VI. P. vi. 1892, p. 321.—77. Massart 
and Bordet. J. d. I. Soc. Hoy. d. Sc. Med. et Nat. de Bruxelles, 1890. 78. Massart 
and Bordet. A. de VI. P. v. 1891, p. 417. —79. Pbkelharing. La Semaine med. 1889, 
No. 22, p. 184. 80. Pfeiffer. See No. 33.—81. Stahl. See No. 35. For fuller 
bibliography consult Massart and Bordet, No. 77. 
VII. On Phagocytosis General Articles 
82. Adami. Med. Chron. Nov. and Dec. 1891.—83. Baumgarten. Ctbl. f. klin. 
Med. 1888, No. 26; Zeigler’s Beitr. vii. 1889; Berl. klin. Woch. 1884, Nos. 50 and 
51. 84. Bitter. Zeitschr. f. Hygiene, iv. 1888, p. 405. 85. Discussion on Immunity 
(Roux, Metsclmikoff, Hankin, Behring, Buchner, etc.). Trans. Internal. Oongr. of 
Hygiene, London, 1891, vol. ii. 86. Discussion on Immunity. Internat. Congr. 
of Hygiene Buda-Pesth, 1894 (Metschnikoff, Roux, Buchner, Denys, etc.), Ctbl. f. 
Bakt. 1894.—87. Discussion on Immunity. Path. Soc. London, 1892 (Woodhead, 
Klein, Mankin, Martin, etc.); Path. Trans. 1892, v.; also B. M. J. of Feb. 20 and 27, 
1892.—88. Lubabsch. Fortschr. d. Med. viii. 1890, No. 17. 89. Lubarsch. Zeitschr. 
f. klin. Med. xviii. 1891, p. 421. 90. Metschnikoff. See Nos. 14 and 51.—91. 
Nieczajeff. Verhandl. das X. Internat. Med. Congress, Berlin, 1890, ii. pt. 3, p. 
54. 92. Sanarelli. Ctbl. f. Bakt. x. 1891, p. 514.—93. Sternberg. Am. J. of 
Med. Sc. April 1881. —For the abundant literature on this subject consult Bitter 
(No. 84) and Lubarsch (No. 88), as also the full bibliography (up to 1892) given by 
Sternberg in his Manual of Bacteriology. New York, 1892, and (to 1895) in his Immu- 
nity, Protective Inoculation, etc. New York, 1895. 
VIII. Phagocytosis in Connection with Pathogenic Microbes of Various 
Diseases (fob Shortness Names of Diseases alone given) 
Actinomycosis:—94. Marchand. Eulenburg’s Realencyclopddie, article “Actino- 
mycosis.”— 95. Bostrom. Zeigler’s Beitr. ix. 1890. 96. Pawlowsky and 
Maksukoff. A. de I’lnst. Pasteur, vii. 1893, p. 544. Anthrax:—97. Hess. Virch. 
Arch. cix. p. 365. 98. Koch. Cohn’s Beitr. z. Biol, der Pflanzen, ii. 1876. 99. 
Lubarsch. Fortschr. d. Med. 1888, p. 4. —lOO. Metschnikoff. Virch. Arch, xcvii. 
p. 502, and A. de I’lnst. Pasteur, i. 1887, p. 7. —lOl. Nutall. Zeitschr. f. Hygiene, 
iv. 1888. —lO2. Petruschky. Zeigler’s Beitr. iii. 1888, p. 357, and Fortschr. d. 
Med. viii. 1890, No. 15. Cholera : —lO3. Metschnikoff. A. de VI. P. viii. 1894, 
p. 529. —lO4. Pfeiffer and Wassebman. Zeitschr. f. Hygiene, xiv. 1893, p. 59. 
105. Cantacuzene. Recherches sur le mode de destruction du Vibrion Cholerique. 
Paris, 1894. Diphtheria ; 106. Gabritchewski. A. de VI. P. viii. 1894. 107. 
Massart. See No. 76. Erysipelas: —lOB. Metschnikoff. Virch. Arch. evil. 1887, 
p. 209, and numerous other observers. Gonorrhoea: —lO9. Neisseb and all subse- INFLAMMA TION 
137 
qnent observers (for bibliography see Sternberg). Hog Cholera: —llO. Metschnikoff. 
A. de VI. P. vi. 1892, p. 289. Leprosy: 111. Metschnikoff and Soudakewitch. 
Virch. Arch. cvii. 1887, p. 228 (and all recent observers). Malaria; —ll2. Golgi. 
Guz. degli Ospitali, 1886, No. 53 (parasites in leucocytes, as distinguished from red 
corpuscles). Mouse Septicaemia: —ll3. Metschnikoff. A. de Vlnst. P. y. 1891. 
Pathogenetic Torulae in Daphnia: —ll4. Metschnikoff. Virch. Arch. xcvi. Patho- 
genic Moulds (Aspergillus, etc.) : —ll5. Bibbert. See No. 65. Pneumonia (Diplo- 
coccus) : —ll6. Gamaleia. A. de VI. P. ii. 1888, p. 445. —ll7. Isaeff. Ibid. 
vii. 1893, p. 260. 118. Tchistovitch. Ibid. iii. 1889, p. 337. Relapsing Fever: 
—ll9. Metschnikoff. Ibid. i. 1887, p. 329. —l2O. Soudakewitch. Ibid. v. 
1891, p. 545. Suppuration (Staphylococcus pyogenes) : —l2l. Fleck. Die acute 
Fntzundung der Lunge. Dissert., Bonn, 1886.—122. Hess. See No. 37. —123. Hohn- 
feldt. See No. 38. —124. Lahr. Ueber d. Untergang d. Staph, in der Lunge. 
Dissert., Bonn, 1887 (and numerous other observers). Swine Erysipelas (“ Rouget ” 
or “ Rothlauf ”): —125. Metschnikoff. A. de VI. P. iii. 1889, p. 289. —126. Schutz. 
Arb. a. d. Kaiserl. Gesundheitsamt, i. 1885, p. 61. —127. Tchistovitch. See No. 118. 
Symptomatic Anthrax (Quarter-evil) : —l2B. Buffer. B. M. J. May 24th, 1890. 129. 
Buffer. A. de VI. P. v. 1891, p. 673. Tuberculosis: —l3O. Borrbl. See No. 58. 
131. Metschnikoff. See No. 51. —132. Stschastny. Virch. Arch. cxv. 1889, and No. 
68. Vibrio Gamaleia vel Metschnikovi: —133. Metschnikoff. A. de VI. Pasteur, v. 
1891, p. 465. —134. Sanarelli. Ibid. vii. p. 225. 
IX. On the Bactericidal Action of the Bodily Humours 
135. Behring and Nissbn. Zeitschr.f. Hygiene, viii. 1890, p. 424. —136. Buchner. 
Arch.f. Hygiene, x. 1890, pts. 1 and 2; Gentrlbl.'f. Bakt. v. 1889, p. 817, and vi. p. 1. —137. 
Emmerich and di Mattei. Fortschr. de Med', vi. p. 729. —l3B. Von Fodor. D. Med. 
Woch. 1887, p. 745; and Ctbl.f. Bakt. vii. 1890, p. 763. —139. Hankin. See No. 150. 
140. Lubarsch. Ctbl.f. Bakt. vi. 1889, p. 841.—141. Nissen. Zeitschr.f. Hygiene, vi. 
1889, p. 487. —142. Nuttall. Ibid. iv. 1888, p. 353. —143. Pekelharing. La Sem. med. 
1892, p. 503. —l4l. Traubb and Gschleiden. Jahresbr. d. Schlesischen Gesell. lii. 1874, 
p. 179. —145. Weigert. Fortschr. d. Med. v. 1887, p. 733.— For other articles consult 
the works of Sternberg previously mentioned. 
X. Upon Extra-Cellular Activity and the Production of Bactericilal and 
Toxicidal Substances prom Wandering Cells, etc. 
146. Adami. See No. 82. —147. Buchner. Fortschr. d. Med. x. 1892, Nos. 9 and 
10; Munch. Med. Woch. 1894; Ctbl. f. Bakt. xvi. 1894, p. 738, and No. 86. —l4B. 
Denys. La Cellule, 1894. —149. Denys and Havel. Arch, de med. exptlle. vi. 1894. 
150. Hankin. Proc. Boy. Soc. xlviii. 181)0, p. 93; Ctbl. f. Bakt. ix. 1892, p. 722; Ibid. 
vols. xi. and xii.; see also No. 85. —l5l. Kanthack and Hardy. Proc. Roy. Soc. 
Nov. 1, 1892. —162. Kanthack and Hardy. J. of Physiol. 1893. —153. Kanthack 
and Hardy. Phil. Trans. 1894. —154. Kossel. Zeitschr.f. Hygiene, xvi. 1894. —155. 
Metschnikoff. A. de VI. P. viii. 1894, p. 706. —156. Pfeiffer. Zeitschr.f. Hygiene, 
xvi. 1894, p. 268, and xviii. p. 1. —157. Bibbert. See No. 65. —l5B. Tizzoni and Cat- 
tani. Berl. klin. Wochenschr. 3. 1894. —159. Vaughan and M'Clintock. Med. Hews 
(N. Y.), Dec. 23rd, 1893. 
XI. On the Part played by the Blood Vessels in Inflammation 
In addition to Cohnheim (No. 6), Hamilton (No. 9), Leber (No. 12), Beckling- 
hausen (No. 16), Samuel (No. 18), Weigert (No. 23), and Ziegler (No. 24), consult 
—l6O. Arnold. Virch. Arch. liv. 1871, on “Development of Capillaries.”—l6l. 
Charrin and Gley. Arch, de Physiol. Oct. 1890. —162. Israel. Lehrbuch d. Path. 
Anat. —163. Samuel. Virch. Arch, xliii. 1868, p. 552, and li. 1870, p. 178 (“Change 
in Vessel Wall, inducing slowing of Current ”). —164. Thiersch. Pitha and Billroth’s 
Chirurgie, 1867, i. pt. 2, p. 529 (on “New Formation of Vessels”). Fuller references 
given in Ziegler (No. 24) and Hamilton (No. 9). i3§ 
SYSTEM OF MEDICINE 
165. Addison. Exptl. and Tract. Researches upon Infl. London, 1843. —166. 
Arnold. Virch. Arch. Iviii. 1872, Ixvi. 1874, and Ixviii. 1876.—167. Bxnz. Virch. 
Arch, lix., Ixxiii., and Ixxxix.; Arch. f. expt. Path. vii. and xiii. —l6B. Cohnheim. 
See No. 6. —169. Disselhorst. Virch. Arch, cxiii. 1888, p. 108. —l7O. Hbring. Wien. 
Acad. Bericht. Ivii. 1868, p. 170 (on the “Adhesion of Corpuscles”). —l7l. Kalten- 
brunner. Exp. circa stat. sanguinis et vasorum in infl. 1826. —172. Kbrner. Pfinger’s 
Archiv, yii. —173. Lavdowsky. Virch. Arch, xcvii. —174. Metschnikoff. See No. 
14.—175. Pekrlharing. Virch. Arch. ci. 1885. —176. Recklinghausen. Strieker’s 
Handb. Article, “Das Lymphgefasssystem.”—l77. Schklarewsky. Pfiuger's Arch. 
i. 1868, pp. 603 and 657.— 178. Thoma. Berl.klin. Woch. 1886. —179. Waller. Phil. 
Mag. xxix. 1846, pp. 217, 298, 397. 
XII. On the Diapedesis of Leucocytes 
(a) On the Effect of Intra and Extra-Vascular “Toxins” upon Diapedesis 
180. Bouchard. Essai d’une the. or in de Vinfection. Verhandl. d. X. Internal. 
Med. Gongr. Berlin, 1890. —lBl. Charrin. Ibid. ii. pt. 3, p. 29. 182. Roger. 
Contrib. a Vetude de Vimmun. acquise, p. 1.—183. Ruffer. A. de VI. P. v. 1891, 
p. 673. The earlier literature of diapedesis is given in detail by Wagner (No. 22) 
and Hamilton (No. 9). The last (German) edition of Ziegler (No. 24) is also very 
full. 
XIII. On the Part played by the Nervous System in Inflammation 
184. Berkley. Anat. Anz. viii. 1893, Nos. 23 and 24, and ix. 1893, Nos. 1 and 
2; Joum. of Comp. Neurol, iii. 1893, p. 107; Pathol. Studies, Johns Hopkins Univ., 
Neurology, ii. 1894 (“Upon Nerve Endings in Vessel Walls, etc.”). —lB5. Charcot. 
Leqons sur les maladies du syst. nerveux. Paris, 1873, p. 106. 186. Cohnheim. See 
No. 6. —lB7. Cache and Malvoz. A. de VI. P. vi. 1892, p. 538 (on “Influence of 
Nervous System in Mycotic Inflammations”). —lBB. De Paolis. Riforma Medica, 
1889, No. 200. —lB9. Frenkel. Arch. d. med. expt. iv. 1892, p. 638. —l9O. Gergens. 
Pfliiger’s Arch. xiii. p. 591. —l9l. Klebs. Ally. Pathol, ii. 1889, p. 384. —192. Len- 
HossE’f. Arch. f. mikr. Anat. xxxix. 1892 (on “Nerve Endings”). —193. Mitchell, 
S. Weir. Injuries of Nerves. Phila. 1872, p. 168. —194. Ochotine. Arch, de med. 
expt. iv. 1892, p. 245. —195. Retzius. Biol. Untersuchungen, Neue Folge, iii. 1891, 
p. 49, and iv. —196. Roger. Gomptes Rend. Soc. de Biol. 3rd May 1890, and 22nd 
Nov. 1890. —197. Rutimeyer. Arch. f. expt. Pathol, xiv. p. 384. —l9B. Samuel. 
Virch. Arch. exxi. —199. Saviotti. Virch. Arch. 1. 1870, p. 592 (on “Dilation and 
Contraction of Arteries according to Nature of Irritant”).—2oo. Sbvbrini. La con- 
trattilita dei capillari, 1881.—201. Wagner, A. Arch. f. klin. Ghirurq. xi. 1869, 
p. 1. 
XIV. On the Part played by the Connective Tissue Cells in Inflammation 
202. Arnold. Arch. f. Mikr. Anat. xxx. 1887.—203. Baumgarten. Virch. 
Arch. Ixxviii. 1879; Ueber Tuberkel und Tuberkulose, i. Die Histogenese des Tuber- 
kulosenprocesses. Berlin, 1885.—204. Borrel. See No. 58.—205. Coen. Ziegler’s 
Beitr. ii. 1887.—206. Cornil and Ranvier. See No. 7. 207. Discussion at the 
Tenth Internat. Med. Cong. Berlin, 1890. (Ziegler, Marchand, Grawitz.) Verhandl. 
ii. pt. 3, p. 1. 208. Fischer. Untersuch. ii. die Heilung von Schnittvmnden der Haul. 
Inaug. Diss. Tubingen, 1888.—209. Flemming. Virch. Arch. Ivi. 1872, p. 146. 
210. Grawitz. D. Med. Wochenschr. 1889. No. 23, on “ Slumbering Cells.” 211. 
Grawitz. Virch. Arch, cxviii. 1889. 212. Griffith, J. J. of Pathol, ii. 1894 
(on “Development o'f Wandering from Fixed Cells ”).—213. Gull and Sutton. Med.- 
Chir. Trans. Iv. 1872, p. 273.—214. Huchard. Traite des maladies du cceur. Paris, 
1889 (on “Dystrophic Sclerosis”).—-215. Krafft. Ziegl. Beitr. i. 1884. 216. 
Marchand. Ibid. iv. 1888. 217. Metschnikoff. Biol. Gentrbl. 1883, p. 561; 
A. de VI. P. vi. 1892, p. 1 (on “Development of Wandering from Fixed Cells ”).—218. 
Nlkiforoff. Ziegl. Beitr. viii. 1890, p. 419. —219. Podwyssozki. Ibid. i. 1884, THE DOCTRINE OF FEVER 
139 
and ii. 1886.—220. Ranvibr. Comptes rend, de VAcad. d. Sc. 1891, p. 843.—221. 
Reinke. Ziegl. Beitr. v. 1889.—222. Roy and Adami. B. M. J. 15th Dec. 1888. 
223. Schbltbma. D.Med. Woch. 1887, p. 403. 224. Sherrington and Ballancb. 
J. of Physiol. 1889, p. 856.—225. Soudakewitch. A. de VI. P. vi. 1892, p. 13. 
226. Stricker. Studien a. d. Inst. f. exp. Pathol. Vienna, i. 1870. 227. Toupbt. 
Des modifications cellul. dans Vinfl. simple du peritoine. Thesis, Paris, 1887.—228. 
Ziegler. Exp. Untersuch. ii. die Herkunft der Tuberkelelement. Wurzburg, 1875. 
229. Ziegler. Untersuch. ii. pathol. Bindgewebs- und Gef'dssneubildung. Wurz- 
burg, 1876.—230. Grawitz, No. 211, gives a very full bibliography up to 1889 of the 
part played by the connective tissue cells. Consult also Virchow (No. 21), Cohnhbim 
(6), Mbtschnikoff (14)', and Ziegler (24). The later German editions of Ziegler’s 
Handbook contain a very judicial discussion of the relationship of fibrous hyperplasia 
to inflammation. 
XV. On the Temperature Changes in Inflamed Areas 
231. Billroth and Hufschmedt. Arch. f. klin. Chirurg. vi. 1864, p. 373. 232. 
Hunter, John. On the Blood, Inflammation, and Gunshot Wounds. London, 1793. 
233. Huppert. Arch. d. Heilkunde, xiV. 1873, p. 73. 234. Jacobson and Bern- 
hardt. Med. Centlbl. 1869, No. 19. 235. Laudien. Ibid. 1869, No. 19. 236. 
Schneider. Ibid. 1870, No. 34.—237. Simon. Holmes’s System of Surgery, 1860, 
article “ Inflammation.” —238. Weber, O. Deutsch. Klin. 1864, Nos. 43 and 44. 
J. G. A.