Its Nature, Causes, Effects, and General Treatment.
The study of inflammation is an old one and many definitions have been proposed as more and more light has been thrown on the pheno mena observed. Celsus drew attention to what are still called the cardinal symptoms of inflam mation, calor, dolor, tumor, rubor, and to these later writers have added a fifth, functio lcesa, i.e. impairment of function. But the observation of these characteristic features in an inflamed area gave no clue to the process, and John Hunter, the celebrated English surgeon, went much further when he defined inflammation as"a process set up by injury and tending to counteraction of the same."Later still Cohn heim studied the vascular changes occurring in an injured part by observing the web of a frog's foot under the microscope. On applying to this delicate, highly vascular, and translucent membrane some irritant such as a drop of an acid certain changes in the flow of blood through the vessels are soon apparent, and Cohnheim was the first to lay stress on these as character istic features of inflammation. But in less vascular areas these phenomena are less marked, and if the injury be of a milder but more pro longed type the chief changes are of the nature of connective tissue overgrowth. With a wider understanding of the whole series of observed changes, Burdon Sanderson of Oxford defined inflammation as"the succession of changes occurring in a part as the result of injury in sufficient to kill the part."Thus we can at the very outset of our study fasten on to the con ception that inflammation is not made up of a series of harmful events submitted to passively by a part of the body subjected to an injury, but is rather a struggle or reaction tending to counteract the local effects of that injury. Two further definitions, terse but comprehensive, due, the former to Adami, the latter to Grawitz, may be given, namely, that inflammation is"the local attempt at repair of injury"or"the reaction of irritated and damaged tissues which still retain vitality." Metchnikoff, in his exhaustive and illuminat ing study of the functions of leucocytes and of phagocytosis, has shown how important these cells are in inflammation, responding as they do with extraordinary sensitiveness to injury. In this particular the leucocytes are very similar to such a simple unicellular organism as an amoeba. It may be well, therefore, to consider this simplest possible case of inflammation (i.e. reaction to an injury insufficient to kill) in a unicellular organism.
To such a simple little mass of protoplasm surrounding a nucleus, living in a fluid medium, such as pond water, the injury will usually be of a chemical nature. Some substance inimical to the amoeba is in solution in the water and at 547once a reaction begins. The cell which was before putting out pseudopodia to envelop any food particles floating within its range, now draws them in and becomes quiescent. It may die as a result of the poison, but by hypothesis such a degree of injury is not contemplated. If it survive it will shortly begin to show signs of renewed activity, moving about, extending its pseudopodia, and surrounding food particles as before. Its recognition of food particles must really be in the nature of a chemical reaction, the food exuding or exhaling some substance into the water which stimulates the amceba to ingest it. This sensibility to chemical agents is possessed not only by unicellular animals but by plant cells and by cells in the bodies of the higher animals, and Pfeiffer applied the name chemiotaxis to this property of cells. It is developed in the body to a remarkable degree as a defence mechanism, as has been shown especially by Metchnikoff. But to continue our observations. Sometimes the amceba may have to wage war against other small organisms, and here again the intelligence will be by means of a chemical stimulus indicating the presence of the enemy and suggesting one of two courses of action. Either the amceba may advance, and proceed to engulf, digest, and destroy the foreign organism, or if the enemy be too power ful or virulent the amceba may retreat, with drawing its pseudopodia, and moving as far away as the medium will allow so long as the presence of the enemy is felt.
Put briefly, our unicellular organism reacts to injury in one of three ways. These are: (1) By adaptation, in which the organism becomes habituated to, or tolerant of, the injurious substance.
(2) By chemiotaxis, that is, the chemical attraction (positive chemiotaxis) or repulsion (negative chemiotaxis) of the organism by the injurious substance.
(3) By phagocytosis, where the organism ingests and destroys the injurious substance or particle.
The adaptation of a cell to an initially dis tasteful substance shows itself by a change from negative to positive chemiotaxis.
If the investigation of inflammation be carried into the range of slightly higher organisms such as the metazoa, in which we have the earliest development of a mesoderm, other interesting phenomena can be observed. The body, covered outwardly by an ectoderm and lined internally by an entoderm, has between these layers a body cavity or ccelom in which, in the lowest types, there is a mesoderm which consists simply of wandering cells. With an injury of such a nature as the entrance of an invading foreign organism into the body, the mesodermal cells at once react to the stimulus, and, in the case of a successful reaction, proceed to crowd round and envelop the invader. The individual mesodermal cells fuse to form a multinucleated mass called a plasmodium, and the foreign body is killed and digested, or simply encapsulated and made harmless. This process of crowding round an invading organism is very similar to the formation of giant cells in the higher animals, as we shall see.
But these simple conditions in unicellular and little differentiated organisms are subject to great modifications in the body of one of the higher animals. In such an animal, as in man, there is a closed system of blood-vessels ramify ing in all directions and carrying a fluid, the blood, which is made up of the liquor sanguinis or plasma, and the blood cells of two kinds, the white and red corpuscles. Propelled by the heart, the blood circulates through the arteries, arterioles, and capillaries practically to all parts of the body, and is returned for the most part by the venules and veins to the heart. Arteries and veins have, comparatively speaking, thick impervious walls through which neither plasma nor cells can easily escape, but the capillaries have walls made up of endothelial cells of only one layer, and both liquid and cells can under certain circumstances leave the vessels and escape into the tissues through the endothelial layer. One of the most important functions of the blood is to convey nutriment, taken up from intestines and lungs, to the cells of all the tissues, and to remove waste products from the tissues to the lungs, kidneys, and other ex cretory organs. In order to supply individual cells some of the plasma laden with nutriment normally escapes from the capillaries, becomes extravascular, and bathes the cells. Exhausted of its supplies the fluid, now called lymph, is taken up by another set of thin-walled vessels, the lymphatics, and by them carried to the main lymph channel, called the thoracic duct, which empties its lymph into the great veins near the heart.
Such are the chief"lines of communica tion,"to use a military phrase, in the body, and the possession of this closed vascular system and subsidiary lymphatic drainage system altogether modifies the process of in flammation. Receiving an injury in any tissue or organ, the body is possessed of interior lines of communication, and is thus enabled to send reinforcements of defending cells and supplies for the repair of the damaged structures.
Further, the casualties resulting from the injury, broken down or dead cells, can be removed along one or other of the two routes. Thus the blood vessels in an inflamed area are very intimately concerned with the reaction which follows the injury, and it was the observation of the re markable series of changes occurring so con stantly in the blood-vessels of an inflamed area which led Cohnheim to emphasize the vascular phenomena almost to the exclusion of all else. Not all tissues, however, are equally vascular, indeed m some there are very few blood-vessels, and here other factors come into play. Again, not all injuries causing inflammation call for the same reparative or defensive measures. It may be well to consider briefly, therefore, what the causes of inflammation are, in order that the appropriate reaction may be understood.
Causes of Inflammation. - Inflammation may be caused by a great variety of injuries, but most of them can be included in one or other of the following: (1) mechanical; (2) thermal; (3) chemical; (4) toxic.
Mechanical injury is frequently seen giving rise to inflammation, as in the case of friction by harness producing inflammation of the skin; stretching or spraining in galloping or jumping causing inflammation of a tendon; a blow or fall bringing about fracture of a bone with all the phenomena of inflammation; or a wound by means of any sharp instrument with a reaction in the adjacent tissues leading to healing of the wound.
Thermal injury, as by burns or scalds, or the injury by an electric spark or by lightning stroke, at once sets up an inflammatory reaction with all the well-marked signs.
Chemical injuries, by means of caustic sub stances such as quicklime or strong acids or caustic alkalies, are very obvious and well known to all. Less well known are the inflam matory reactions caused by chemical irritants within the body acting on tissues with which they come in contact. Cantharides given in ternally, or absorbed from a too - plentiful application to the skin, is excreted through the kidneys and urinary tract, and gives rise to acute inflammation in the kidneys and bladder. Alcohol passing through the liver in frequent small doses is a chemical irritant, and results in a chronic inflammatory reaction in that organ. A fairly common weed - Senecio Jacobcea or"Ragwort"- eaten by cattle on rough pasture for several weeks or months produces a very similar reaction in the liver, in much the same way and with equally serious results.
There are very great differences between the acute reaction with great pain, heat, redness, and destruction of tissue caused by the application of a strong mineral acid to the skin, and the chronic reaction with a painless and slow development of fibrous tissue crushing out the degenerated liver cells brought about by the frequent use of alcohol. Both reactions are, however, examples of chemical injury causing inflammation, and between these two extremes all gradations of injury and reaction may be seen.
Toxic injury is possibly the commonest type of injury producing inflammation. It is brought about by the presence of bacteria in the tissues as a result of the infection of a wound or bruise, or as part of a general infectious disease. The bacteria, having been introduced into a wound or having invaded a tissue from the blood stream, proceed to multiply and to obtain nutriment from the tissues. Growing and multiplying in this way they produce toxic substances or toxins, as excretory products of their metabolism or as the result of active secretion, and these toxins straight away call forth a reaction on the part of the tissue infected - in other words, they produce inflammation. Thus we may look upon toxic injury by bacteria as a special form of chemical injury. Either as a result of the original wounding or as a conse quence of the toxic action of the infecting bacteria, a portion of the tissue attacked may die. The dead tissue is probably already invaded by the bacteria, or it is disintegrating and dissolving under the ferment action of its own juices. In the former case the bacteria in the dead mass will continue to produce toxins which will irritate and injure the adjacent living tissue, whilst in the latter the breakdown products themselves are often highly injurious and irritant to living cells. Thus a piece of dead tissue will, whilst still embedded in a living tissue, continue to act as an irritant, producing chemical injury and inflammation.
Injury by toxins brings about a reaction in much the same way as other chemical irritants, but there is an extremely important difference. So long as the bacteria producing the toxins remain alive in the tissue so long will they go on multiplying, and the supply of toxin will be kept up, so that whilst a mechanical injury such as a blow is inflicted and then ceases after a longer or shorter time, a bacterial or toxic injury goes on indefinitely, and with increasing severity, unless the reactive processes are able to subdue and expel the invading organisms.
Reactive Resources of the Body. - From a con sideration of the foregoing statement of the causes of inflammation it is possible to realize the demands put upon the defensive and amelior ative forces of the body which has been injured at some point. If the injury is of a very mild type, but continuing over a long period of many days or weeks, then the tissue attacked will probably be able to supply from among its own cells those that are necessary for successful reaction. Such a reaction is seen in the forma tion of a fibrous tissue capsule round a parasite, such as a hydatid growing in liver or lung. On the other hand, with a suddenly occurring injury of a severe character, the resources of the part are inadequate, and must be reinforced rapidly. Here the blood-vessels, the interior lines of communication, are of inestimable value, and signs of effort on their part are very evident. It was these signs which Cohnheim observed in his study and described as the vascular phenomena of inflammation.
Vascular Phenomena. - To study these changes a frog's web or a frog's tongue may be used.' In the first few minutes following injury there is a local contraction of the arterioles, and so a temporary blanching of the part. This is speedily followed by a progressive arterial dilatation, bringing about a greatly-increased flow of blood through the area. This distension spreads down to the smallest vessels, and capillaries previously invisible are now easily detected. Such a distension of the vessels of the part may be seen within half an hour of the injury in the frog.
Meantime there is a gradual slowing of the current of the blood stream. On first sight the current was so swift that individual cells could scarcely be seen, but there was a blurred stream of red cells rushing on in the centre of the vessel, and a clearer zone of plasma on each side. Now the current is slower, the axial stream has broadened out, and individual cells can now be distinguished. The red and white cells can be differentiated, and it is seen that the white cells (leucocytes) are tending more and more to the outer or peripheral part of the blood stream.
By the time this stage has been reached in the blood stream of an inflamed area, the part itself is beginning to appear swollen. Experi mentally, by putting a fine tube into one of the main lymphatic vessels it can be shown that corresponding with this stage there is a greatly increased outflow of lymph from the blood vessels into the tissues as compared with the normal. This lymph drips out from the tube or cannula much more rapidly than from a normal uninflamed area.
But to return to the blood-vessels. The white cells or leucocytes in the outer zone of the blood stream are now seen to be increasingly numerous, and they arc beginning to adhere momentarily to the side of the vessel, just as twigs floating along in a slow stream catch against the bank. The current becomes still slower and eventually numbers of leucocytes adhere to the side of the vessel and the current comes almost if not quite to a standstill. This condition of stasis affords an opportunity to watch some of these adherent leucocytes. Not only are the leucocytes very numerous inside the capillary, but a number may be seen outside the vessel in the neighbouring tissues, and in a suitable preparation the actual passage of these white cells through the vessel wall may be observed. The adherent cell puts out a process which penetrates between adjacent endothelial cells of the capillary wall, and the process grows larger and larger on the outside till all the cell has squeezed through and is free to wander outside the vessel in the inflamed tissue. This process is called migration or diapedesis.
The leucocytes or white cells of the blood are not all of one type; there are several varieties. The chief types actually concerned in inflamma tion are: (1) the polymorphonuclear leucocytes, fairly large cells with a bi- or tri-lobed nucleus, and a fairly wide ring of cytoplasm round it; (2) the lymphocytes, small cells with a mono lobular nucleus nearly occupying the whole cell and leaving a very narrow encircling ring of cytoplasm; (3) large mononuclear leucocytes, with a round or oval rather faintly-staining nucleus, and a considerable ring of cytoplasm; and (4) the eosinophils, fairly large cells whose nucleus is obscured by granules in the cytoplasm, which granules stain readily with acid stains such as eosin.
In an acute inflammation it is especially the polymorphonuclear cells which migrate, but in special conditions and in more chronic cases lymphocytes, large mononuclears, and eosino phils may all pass through the vessel-wall. Diapedesis does not occur in arteries, but only in thin-walled vessels such as capillaries and small veins. The escaped leucocytes may wander a considerable distance among the tissue elements from the place where they escaped. In all severe inflammations some red corpuscles as well as leucocytes escape, but probably this is purely mechanical from serious injury to the vessel-wall allowing of leakage.
The fluid which escapes from the vessels con stitutes what is called the inflammatory exudate. It saturates the tissues and solid organs, dis tending their lymph spaces, and so bringing about the characteristic swelling in the inflamed area. In the case of an inflamed membrane, such as the skin, or pleura, or peritoneum, the exudate escapes from the free surface and accumulates in any cavity bounded by the membrane. Thus, in cases of pleurisy the fluid in the chest cavity is an inflammatory exudate which has transfused from the damaged pleura. Such an inflammatory exudate is usually more or less turbid from its contained leucocytes, and sufficiently rich in fibrin for a thinner or thicker layer of coagulated whitish-yellow lymph to be deposited on the free surface, and for stringy shreds or flocculi of lymph to float in the fluid.
To find an explanation for these various phenomena it is necessary to realize the extreme sensibility of the endothelial cells of which the capillary vessel-walls are built. The injury, whatever its nature, has caused damage to these sensitive cells, and so the capillary tube instead of being almost frictionless now opposes the flow of blood.
Thus the current is made slower, and the leucocytes have got something to adhere to. The dilatation of the vessels of the part is largely under the control of the (vaso-motor) nervous system. The accumulation and migration of the leucooytes is not merely a mechanical process, but quite definitely a vital one. Pos sessing the characteristic property of chemio taxis, the white cells of the blood scent out the damaged cells of the injured part, and are particularly attracted by certain common bac teria often present in wounds. The leucocytes are amceboid and can protrude pseudopodia, the distended vessel - wall is stretched, and possibly the cement substance uniting the adjacent endothelial cells is less resistant than normal, and so the active leucocytes first adhere to and then penetrate the capillary wall to seek out the invading micro-organisms in the tissues outside. Thus the richness of an inflam matory exudate in cells depends on the degree of attraction for leucocytes outside the vessels. In cases where suppuration or pus formation occurs as a part of inflammation it is because the leucocytes show great positive chemiotaxis towards the chemical products of the causal bacteria. On the other hand, some highly virulent bacteria secrete products which exert great repelling effects on the leucocytes, and in such cases any inflammatory exudate is poor in cells. In still other cases, although there is no marked repulsion of leucocytes there is no active chemiotaxis on their part for the bacterial toxins or other products of the injury, and so again the inflammatory exudate is free from cells and thin.
The exudate itself may be extruded from the vessels to some extent mechanically as a result of the congestion and the stretched capillary walls. Much more reasonable is the view that just as Heidenhain supposes the endothelial cells of the vessel-walls to secrete the ordinary lymph required for the nutrition of the normal tissue of the part, so in inflammation the endo thelial cells secrete an excess of fluid for the purposes of repair.
The explanation of the cardinal symptoms follows naturally from what has gone before. The swelling - tumor - has already been ex plained as due to the excess of fluid or exudate. The redness - rubor - and the heat - color - are both due to the congestion and distension of the blood-vessels of the area. The pain - dolor - is in large measure, if not altogether, due to the pressure exerted by the exudate and the congested blood-vessels on the nerves and nerve endings in the part, and with relief of tension, such as occurs when an abscess is opened, there is great lessening of the local pain.
Thus by means of the blood-vessels great reinforcements of leucocytes and plasma or lymph have been transported to the actual fighting line where the damage to the normal cells is taking place. Assuming the case to be one of bacterial invasion of the tissues as the result of a scratch or wound, the question arises as to the exact role of these reinforcements. How do they act ? In the case of the leucocytes, chiefly of the polymorphonuclear variety, their function is to mass round about the invading bacteria and proceed to ingest them. In other words, these leucocytes are active phagocytes, and in a stained specimen from such an inflamed part many of these cells are seen to have bac teria inside them.
That the bacteria are ingested while still alive is shown by the fact that the leucocytes con taining them may be used to infect culture media, when the ingested bacteria will grow and multiply.
The exact effect of the plasma forming the inflammatory exudate is not so easy to demon strate and is to some extent still a matter of controversy. That it has an important func tion in supplying extra nutriment to the cells of the part which are actively engaged in defence and repair will be easily understood. But that is by no means its only function.
The following facts will help to an under standing of the important part the exudate plays. Even in 1881 Lister had noted that drawn blood was able within certain narrow limits to arrest the action of putrefactive bac teria. Many observers studied this matter and Pfeiffer at length described the phenomenon of bacteriolysis. He showed that if a guinea-pig was made immune by the repeated inoculation of small doses of a virulent micro-organism such as the cholera spirillum the animal's serum became possessed of a new property, that of dissolving and destroying these virulent bac teria. In an actual experiment an immunized guinea-pig had a large dose-5 to 10 times the ordinary fatal dose - of cholera germs injected into the peritoneal cavity, and on removing by means of a pipette small quantities of the exudate which formed in the peritoneum it was seen that the introduced bacteria were first rendered motionless and then gradually dis solved by the fluid. This is not only the case with cholera but with other pathogenic bacteria, against which an animal or man may have been rendered or become immune. Further, there is good evidence that normal blood serum possesses this property of bacteriolysis in some degree against many bacteria, and it was this property that accounted for Lister's observation.
It will be evident that the whole series of inflammatory phenomena which have been thus far described as resulting from the invasion of a part of the body by bacteria are directed to one end, namely, a defence of the tissue by the bringing up of reinforcements intended to attack and destroy the invader. In other words, the body proceeds to develop a counter-offensive by means of its phagocytes and bacteriolytic serum.
But, as a result of the first attack or injury, there have been some casualties. Some of the cells of the damaged tissue have actually been killed, whether by mechanical injury as by division in the case of a cut by a knife, or by burning in the case of thermal injury, or by the toxic action of bacteria in cases of septic infection. These dead cells may be very few in the case of a clean-cut wound, or very numerous in the case of au extensive bruise or burn, or in a severe bacterial invasion of an organ. In most wounds there is, in addition, the escape of more or less blood, and the blood clot which is formed is simply a mass of dead tissue consisting of fibrin entangling red blood corpuscles. Further, apart from the original injury, the damaged tissue may be invaded subsequently by bacteria, and these will wage war not only on the cells of the part, but also on the leucocytes which migrate into it for offensive or defensive purposes. Thus, in any inflamed tissue there are to be found numbers of dead cells, made up of cells of the tissue itself, extravasated blood, and leucocytes attracted to the part. There is, therefore, something more required than the mere overthrow of the agent responsible for the damage, be it chemical or bacterial, for dead cells themselves act like' foreign bodies and continue the irritation and injury of neighbouring living tissues. Dead cells or dead tissues do not remain unchanged, for disintegration and decomposition follow death. This disintegration is brought about to a large extent by the invading bacteria, if such are present, but even in the absence of bacterial infection the dead cells themselves contain ferments which split up the complex material (protein) of the cell substance into simpler bodies. Many of these breakdown products are poisonous and are of similar composition to ptomaines. These chemical poisons, the pro ducts of dead cells, continue to irritate the surrounding living cells and keep up and even extend the inflammation in the part. Thus it is essential that dead cells and dead tissue should be dealt with in the course of the reaction.
There is also required the repair of the actual loss of tissue resulting from the injury. In the case of an extensive wound or burn this may be considerable. In the case of fracture of a bone new tissue is required to effect union. In inflammation of internal organs and structures there is also some breach in the continuity of the structure to be made good. Thus regenera tive growth with repair or rebuilding of the damaged tissue is a further important part of the inflammatory reaction. The resources of the body for these necessary functions must now be considered.
Reparative Phenomena. - Inflammation, as we have seen, is an effect or reaction, and it tends to cease when the cause - an injury of some kind - ceases to operate. The abnormal vas cular phenomena gradually subside, exudation into the part ceases, the circulation through the area is revived, the migration of leucocytes out of the vessels diminishes, and repair of loss of tissue begins An initial stage is the clearing of the ground. Firstly, there is the inflamma tory exudate to be removed. If liquid, as in the case of pleural or pericardial fluid, it is reabsorbed by the lymphatics and veins. If coagulated into a solid fibrinous lymph, whether on the surface of a membrane such as the pleura or peritoneum, or forming a solid plug in a small cavity such as an air space in the lung, it is got rid of by a process which combines disintegra tion by ferment action, and ingestion and removal by large numbers of leucocytes. Dead cells, if comparatively few in number, are removed similarly by the agency of leucocytes which ingest them. In this process the large mononuclear leucocytes take a prominent part. If instead of a few dead cells there is a mass of dead tissue the two processes of breakdown by ferments and invasion and ingestion by leuco cytes go on together. By these means the mass of dead tissue is gradually separated off from the adjoining living tissue, and if near the surface of the body the dead-piece may slough off. Such is the common result in the case of a superficial burn, or a bed sore, or a severe saddle gall on a horse's back. If the dead tissue is deeply situated it will be either completely ingested by leucocytes and removed piecemeal, or if too large for this it will set up, as a result of the chronic prolonged irritation due to its presence, another type of reaction on the part of the living tissues. This has for its object the complete shutting off of the dead tissue, by the formation round it of a capsule of connective tissue.
Regenerative growth to supply the loss of tissue results from the germinal activity of the uninjured living cells of the part. The cells of all tissues do not possess this power of regenera tive repair to an equal extent. It is especially well developed in simple connective tissue - white fibrous tissue - and in the endothelial layer of the wall of blood-vessels. New fibrous connective tissue is formed in the same way as the original normal connective tissue, namely by the agency of fibroblast cells, the descendants of connective tissue corpuscles. It is possible that some of the migrated leucocytes may also take on this function and become fibroblasts (Metch mkoff). For the repair tissue to be adequately nourished it must be provided with blood vessels, and in the formation of these the endo thelial cells of existing vessels play the chief part. If a capillary vessel at the margin of an area undergoing repair be observed it is found that conical buds arise at intervals and by rapid multiplication of the endothelial cells a number of solid endothelial processes project from the wall of the vessel. As each process grows it becomes hollowed out at the base and blood enters and distends it. The process may come in contact with another similar process so as to form a loop or it may bend back and rejoin the parent vessel. By this means a series of capillary loops are formed. Outside the endo thelium of these new vessels are young fibro blasts forming new connective tissue layers, and so arteries and veins are provided in the new tissue.
Epithelium and periosteum are also possessed of the power of regenerative repair in a high degree, so that if the surface of a mucous mem brane or that of a piece of bone is denuded, the epithelial or periosteal cells outside the injured area grow in to cover over and make good the defect. On the other hand, muscle tissue possesses this power to a very slight extent, and nerve cells probably not at all. To study these later stages of inflammation recourse must be had to microscopic sections made through injured parts showing different degrees of injury and the reactions provoked by them at all stages. The healing of wounds and the repair of fractures of bones also illustrate many of the processes, being in fact important types of inflammatory reactions.
Healing of Wounds. - In the simplest case where without bacteria entering there is a simple section of tissue with destruction of a number of cells and injury to others, and where the wound is either so small that the edges come together or are kept in apposition by surgical means, healing takes place by the method known as"first intention."There is at first an oozing
of exudate or lymph, an escape of leucocytes and probably some red cells. Fibrin is formed and a clot fills up the small space between the apposed edges forming the"provisional cement substance."Within the next twenty-four hours the tissue cells bordering on the wound enlarge, send out processes, and divide, so effecting a bridging of the gap by means of these inter lacing cells. The debris of dead cells and blood clot is removed by wandering phagocytes, chiefly mononuclear leucocytes. The capillaries on each side of the gap put out endothelial buds which become hollowed out to form vessels and in a few days the wound is healed.
A shallow surface wound or abrasion heals in a very similar manner"under scab."The scab is made up of desiccated blood-clot or exudate enclosing a number of dead cells. It acts as a support holding the parts together, and since it is hard and quite dry it is also a protective covering in which bacteria cannot propagate.
If there has been more loss of tissue, whether at the surface of the body as in the case of an extensive lacerated wound, or in the depth of some internal organ by reason of some cause, usually bacterial, leading to death of a large mass of tissue, the process will be somewhat different. Considering first a deep-seated mass of dead tissue, we have seen that this will keep up a continuous irritant action on adjacent living tissues especially if infected with viru lent bacteria. Into the zone just outside the dead tissue leucocytes will come crowding. The bacteria in the dead tissue will be most active in the zone adjoining the living tissues, for they are constantly seeking to extend their raids into more and more of the healthy tissue. Thus this junction of living and dead tissues is the battle-ground between the leucocytes and bacteria, and many leucocytes are destroyed in the fight. As they are disintegrated they set free a protein-digesting ferment similar to trypsin, and this digests the dead tissue with which it comes in contact. Meantime the living leucocytes are ingesting both bacteria and dead tissue cells, and so by a combination of the digestive action of the ferment and the phago cytic action of the leucocytes the mass of dead tissue is cut off from the living tissue. If near the surface of the body the dead tissue is called a slough, and its separation leaves an open wound which will heal by the method of granu lation. If deep-seated, the dead piece is called a sequestrum, and it lies more or less free in a cavity with a liquid or semi-liquid material round it, containing the debris of dead tissue cells, dead leucocytes, and dead bacteria.
But all the bacteria in the cavity may not have been killed, and in that case they will be seeking to extend their conquered territory.
In any case the poisonous products of the dead tissue breakdown are injuring neighbouring living tissues, and so the body must interpose a barrier to completely shut out the irritants, whether living (bacteria) or dead (poisonous breakdown products). This barrier is built up of the same materials as, and in a similar fashion to, the scar tissue which fills the gap in an open wound. We can therefore look upon the for mation of a fibrous tissue capsule round a dead mass as essentially the same process as the healing of an open wound by the method of"granulation." If the cut surface of an open wound be care fully observed it will be noticed that at first the divided tissues are distinct, but that they are congested with blood, and a considerable amount of clear lymph is exuding. After one or two days this exudate becomes thick and opaque, and if it be examined microscopically it is rich in cells (leucocytes). On the third or fourth day the wound surface has a characteristic granular appearance from the presence of large numbers of minute red points forming a covering like velvet pile. These are the commencing"granulations"and they are bathed in the exudate still more or less opaque from its con tained cells. If a microscopic section through the granulation tissue be examined it will be seen that each granulation contains one or more endothelial loops budded out, as already de scribed, from the wall of a capillary. Round these minute blood-vessels are cells, either one or other type of leucocytes, or fibroblasts. In the connective tissue bordering on the wound are connective tissue corpuscles, and these by repeated division under the stimulus of the injury give off wandering cells which migrate into the granulations to become fibroblasts. In addition it is possible that some of the migrated leucocytes, notably the large mono nuclears, take on this function, and the vessel endothelium may also supply cells to act as fibroblasts.
Whatever their origin these fibroblasts in the younger superficial layers are rather large, roundish cells with a round or oval nucleus in the centre of the cell. In the older layers at the base of the granulation the fibroblasts have become spindle-shaped, or stellate, and fine fibrillar processes project from them. Gradu ally the cell protoplasm is used up in forming these fibrillar processes until the nucleus is left almost bare. In between the cells there is now laid down an intercellular substance prob ably secreted from the cells, and in it fine fibrils develop. In this way white fibrous connective tissue or scar tissue is formed. It is at first vascular, and plentifully supplied with nuclei, but in older formations it is much less vascular, more fibrous, and has fewer cells in it. Further, the older it gets the more it shrinks, becoming denser and paler from the squeezing out of the unnecessary capillaries. Thus, by the growth of granulation tissue the wound cavity is filled up with connective tissue which gradually contracts down into firm scar tissue. Meantime the epithelial cells at the skin margins are multiplying or proliferating, and tending to creep in over the surface of the granulation tissue. The young epithelium appears as a delicate bluish-pink pellicle, and it gradually extends in from the periphery until, if the area is not too large, it covers the whole surface, when the wound may be said to be healed. In the case of very large wounds the growth of epi thelium is unable to cover the surface before dangerous contraction of the granulation tissue has occurred. Unable to obtain an epithelial covering the scar tissue contracts and often produces very serious distortion of the part. Such an occurrence is frequently seen after extensive burns. To avoid this the parts must be maintained in proper position by splints or bandages, and skin grafts must be used to cover the raw surface. Every little island of living epithelium which can be got to take root upon the granulation area will extend in all directions, and by the coalescence of a number of such islands the surface will be covered with epi thelium.
Returning to the consideration of the mass of dead tissue deep-seated in some organ or tissue, it will now be understood that the fibrous capsule that shuts it off from the surrounding healthy living tissue is formed in an exactly similar fashion to the scar tissue filling in a wound. The granulations now line a cavity in which the dead tissue lies. If the dead mass is small it may gradually be ingested by leucocytes or digested by ferments, and the granulation tissue extending in on every side may fill up the cavity. If the dead mass is too large for this it will either remain as a dry, yellowish-white rather tough amorphous material, or it will break down into thick liquid pus. This pus consists of the broken down tissue and of large numbers of degenerated leucocytes. By absorption of its liquid contents and the gradually increasing pressure of the contracting capsule the pus becomes inspissated, i.e. paste-like or even dry and firm, so as to be crumbly when cut into. The capsule of fibrous tissue may be of consider able thickness; its wall is dense and almost avascular, and the contents are generally sterile, all the bacteria having been destroyed.
In both these cases, the large open wound, and the internal bacterial infection with the death of a larger or smaller mass of tissue, we have assumed the bodily inflammatory reaction to be adequate to effect on the one hand healing and on the other encapsulation of the dead tissue. But the reaction is not always adequate or successful, nor is it always of the same kind. We must therefore consider more fully different types of reaction and their results.
Types of Inflammatory Reaction. - The re action necessary to overcome and repair the results of an injury will depend mainly on the particular organ or tissue injured and on the cause of the injury. Dealing first with the latter, we can make the broad distinction into injuries involving bacterial invasion and those in which there has been mechanical or chemical injury only, without either primary or secondary infection with bacteria.
As an example of purely mechanical injury we may consider a surgical wound made in the course of an operation with all the modern precautions for preventing the entrance of micro-organisms. Such a wound with proper closure heals in the manner described,"by first intention."Again, a simple fracture of a bone is uncomplicated by bacterial infection. Some of the bony tissue has been destroyed; there has been some escape of blood, which remains as dead tissue; muscles in the vicinity may have been injured and some muscle fibres killed. Here the reaction is very similar to that seen in healing by granulation. Exudate is poured out between and around the ends of the two fragments; leucocytes invade the part to ingest and remove the dead tissue; and active bone-forming cells (osteoblasts) come in from the periosteum and from the bone marrow to build up new bone, using the plastic exudate, which in the meantime is assisting to hold the fragments together, as a scaffolding.
A sprained tendon is another example of un complicated mechanical injury. Fibres have been ruptured, some blood has escaped at the seat of injury, and considerable inflammatory exudation usually follows. The inflammatory reaction consisting of the phagocytic clearing-up work of the leucocytes, and the reuniting or welding of the severed fibres by means of new fibrous tissue formed by fibroblasts, generally completes the repair provided that the part is kept at rest. With considerable damage the amount of repair tissue needed is also consider able, and its subsequent shrinkage accounts for the frequently observed contraction following a sprained tendon.
By far the great majority of injuries are, however, either directly due to bacterial infec tion, or if mechanical in origin they are com plicated later by bacterial invasion of the injured part. Much will depend on the particular bac teria concerned, for these organisms differ in virulence very greatly, and consequently in the inflammatory reactions they give rise to. Some organisms of high virulence so overwhelm the defences of the body that practically no reaction occurs. The anthrax bacillus in cattle is an example, for this organism by whatever channel it obtains an entrance rapidly invades the blood stream and the animal dies of septiccemia. In man, anthrax is less virulent so that infection by means of a superficial skin wound or scratch does set up an inflammatory reaction in the form of increased blood flow (hyperaemia), exu dation, and a barrier of leucocytes ("malignant pustule").
Other bacteria are less formidable. To infec tion with this class - the common pyogenic organisms - the reaction is rapid and effective, i.e. they cause acute inflammation. The chief feature is the extraordinary migration of poly morphonuclear leucocytes into the invaded area, so that the bacteria are surrounded by armies of white cells and an abscess is formed.
Still a third class of bacteria may be men tioned whose powers of injury are more or less evenly balanced against the defensive reactions of the body. Here the fight is a prolonged one, in other words, the inflammation remains chronic. Such a condition is seen in most cases of tuberculosis and in actinomycosis.
Of the acute inflammatory reactions there are several types distinguished, mainly by the extent of the leucocytic migration from the vessels of the inflamed area. In the serous type there is abundant exudation but few cells. In the suppurative type there is an immense dia pedesis of white cells, with the formation of pus. Between these two extremes is a type of inflam mation often called fibrinous in which there is abundant exudate and subsequent moderate invasion with leucocytes. Such is the type commonly seen affecting the serous membranes, pleura, pericardium, and peritoneum. The bacterial irritant causes widespread damage and even death of the layer of endothelial cells covering the membrane. The exudate, with some leucocytes in its meshes, coagulates on the surface, forming a protective layer. When the causal bacteria are destroyed and resolution commences phagocytes come in to remove the debris of the fibrinous layer, whilst the remaining living endothelial cells multiply and proceed to spread a new endothelium over the previously inflamed surface. If the damage is more exten sive with destruction of all the endothelium, the fibrinous layer is replaced by granulation tissue, and if this occur on both parietal and visceral surfaces of the membrane, fibrous adhesions or bands passing from one surface to the other are likely to form.
When acute fibrinous inflammation affects a mucous membrane such as that lining the larynx, intestine, or bladder, the irritant or injury usually gives rise to necrosis or death of the surface layer. There is at the same time great engorgement of the capillaries and of the membrane with exudate, and this, together with dead or dying cells and leucocytes, coagulates on the surface to form a"false membrane."At first this is firmly attached to the subjacent living cells so that detachment is difficult and causes bleeding. Later, the phagocytes separ ate off the dead from the living, and so occurs the detachment of the"false membrane."This is the croupous, or diphtheritic, or mem branous type of inflammation.
A slighter degree of injury of a mucous membrane will cause catarrhal inflammation. Here the chief feature is irritation rather than necrosis of the superficial layer. The surface cells are stimulated to rapid division (prolifera tion), and the newly-formed cells are cast off (desquamation) into the exudate. The vessels of the part are greatly distended, there is con siderable exudation, some leucocytes are thrown out, and characteristically the epithelial cells secrete a large amount of mucus.
Thus a liquid layer consisting of exudate, mucus, leucocytes, and desquamated epithelial cells covers the surface and is to some extent protective and bactericidal. With removal of the irritant the phagocytes clean up the dead cells and coagulated exudate, and a new epithelial layer is formed by proliferation and spread from any undamaged epithelial cells left.
The suppurative type of inflammation is char acterized by the great migration of leucocytes into the injured area. Many of these cells die in the struggle with the bacteria, though they are not at once disintegrated and dissolved, but remain. Thus there is formed a thick, creamy, opaque fluid called pus which on micro scopical examination is seen to be a suspension of leucocytes in a fluid, the inflammatory exudate. Some of the cells stain well and may be seen to contain ingested bacteria; others have broken-down, badly-staibing nuclei and are degenerated or dead cells. If the cells are filtered off a thick albuminous fluid is left. When a quantity of pus is confined in a circum scribed space the condition is known as an"abscess."Because of the tryptic ferment in pus and by reason of the pressure it develops an abscess tends to point, i.e. to come to a head in the direction of least resistance. If near the surface of the tissue it bursts, its contents are evacuated, and in a favourable case the cavity fills up by the growth of granulation tissue from its walls. In other cases, as we have seen, collections of pus tend to become encapsuled with a fibrous tissue wall.
A somewhat similar type of inflammatory reaction occurring in an area covered by mucous membrane or skin usually results in an ulcer. The surface cells die as a result of the initial injury or of bacterial infection, and these dead cells are cast off. Thus a raw infected surface is left, and as the bacteria multiply, more and more cells die so that the ulcer extends both in area and depth. With many infections leuco cytes invade the area in large numbers; there is an exudation of lymph from the vessels; and as a consequence the surface is bathed in a layer of pus. The digestive ferments of the pus destroy more and more of the superficial cells and this again continues and extends the ulcer. Ulceration is especially liable to occur in situations or in tissues where the circulation is deficient. In the dog it is quite common to get ulceration of the tip of the tail or the tips of the ears. In these cases bacterial infection may occur secondarily and help to continue the inflammatory process, but the condition is due primarily to a mechanical injury m a part where the blood flow is insufficient to promote healing by bringing up plentiful supplies of fresh lymph. In other cases of ulcer the bac terial infection is the primary cause, and until the bacteria have been destroyed they will continue to destroy, cell by cell, layer by layer, and the ulcer will continue.
Ulcers are much more difficult to treat in old or debilitated or anaemic patients than in young vigorous ones. Lastly, any mechanical im pediments to the free flow of blood through the part, such as tight bandaging, or the upright posture in the human subject affected with ulcers on the leg, or the existence of varicose veins, are against successful treatment. The methods required in such cases are destruction of the infecting micro-organisms by antiseptics or other means; improvement of the circulation through the part; support of the dilated vari cose veins of the part by very gentle pressure; and toning up the constitution of the animal.
One other type of ulceration must be clearly distinguished from these inflammatory ulcers just described, and that is ulceration due to malignant tumours such as carcinomata. The ulcers so caused are not inflammatory in origin, although they may become inflamed secondarily, as a result of infection with bacteria. The point to be thoroughly grasped, however, is that dis infection with destruction of all the bacteria, and improved circulation through the part to promote repair, will not effect healing and cure in the case of these malignant tumours.
In some cases of suppurative inflammation the abscess may be deep-seated, but the pus burrows through the tissues and eventually comes to the surface through a longer or shorter channel called a sinus. The sinus may be simple or direct, or it may be winding, and have off-shoots or side-tracks eaten out in the tissues by the digestive action of the pus or its con tained bacteria. In any case, the sinus almost always has a somewhat thick wall of callous fibrous tissue. This has been built up by fibro blasts belonging to the healthy tissues through which the pus was making its way in order to wall off infection from themselves. Such a sinus shows little tendency to close even after it has opened on to the surface and discharged the abscess contents. In the first place, the thick wall does not easily collapse and close the channel. Secondly, it is very likely to retain bacteria in its lining, for it is not any longer very vascular, and leucocytes and lymph do not easily penetrate its thickness to reach the invading organisms. Not till this callous non-vascular infecting pipe has been dissected away will the sinus heal up.
Even when this has been done success may not be achieved in some cases, for there may still remain that source of chronic irritation already described - a piece of dead tissue in the abscess cavity or at the depth of the sinus. Hard resistant tissue such as bone or cartilage, when killed off by injury, bacterial or mechanical, is particularly likely to cause a chronic discharging sinus. For this reason it is necessary to probe carefully such a sinus, and if dead bone, rough and grating to the probe, is discovered, its re moval by operation is the first step in treatment.
Inadequate Reaction. - And now there remain those cases in which the attempt to cope with the injury, and especially the continuous injury due to chronic bacterial infection, is insufficient. Chronic inflammation may be the result with a gradual increase in extent of the damaged or destroyed tissue until the animal dies exhausted. Such is often the case with tuberculosis of the lungs. Infection occurs and the bacillus of tuberculosis begins to multiply in the lung tissue, gradually extending its range and pene trating further into the adjoining sound portions of the lung. The reaction of the tissues is not very active, there is a migration of leucocytes into the area, especially of lymphocytes, and there are large numbers of epithelioid cells which may have originated from the large mono nuclear type of leucocyte or from connective tissue corpuscles, or from the endothelial cells of the capillaries. The most interesting feature is, however, the presence of giant cells, usually as large as five or six leucocytes together. These cells have multiple nuclei arranged in a ring or crescent round the edge of the cell and they often contain many tubercle bacilli which they have ingested and are attempting to destroy. We have here a structure very similar to the"plasmodium"seen in primitive types. The bacilli may be destroyed to a large extent but usually many of the tissue cells die and a sufficient number of organisms remain alive to extend the area of the disease. The tissues may in a few cases react sufficiently to erect fibrous tissue barriers, but the infection even then often remains virulent, only awaiting a favourable opportunity to escape and become active again.
Besides tuberculosis there are other cases m which the enclosing wall of fibrous tissue may be insufficient for the same reason, viz. that there remains virulent (i.e. infective) material inside the enclosure. This material insidiously but continuously seeks to escape by attacking the wall cell by cell. At length, usually when some abnormal strain is put upon the tissue, the capsule becomes permeable and the virus either sets up another focus of infection in that animal, or is voided some way and infects other susceptible animals. Such cases occur sometimes in horses which have (apparently) recovered from pneumonia, and much more commonly in cattle recovered from one attack of contagious pleuro-pneumonia. Hard work, poor feeding, over-driving, or the coexistence of some other disease such as tuberculosis in the lung, may all be held to account for the"light ing-up"of the old infection, but the essential reason is that the infecting virus was not com pletely destroyed after the first attack of the disease, but has lain more or less dormant inside the insufficient fibrous tissue barrier.
Still another type of chronic inflammation is exemplified by arthritis - inflammation of a joint. Horses used for hard or fast work often suffer from arthritis as a result of the frequently repeated concussion. The pastern joints, the hock, and the stifle are commonly affected. In the great majority of these cases there is no bacterial invasion, but the injury is purely mechanical.
The tissues surrounding the joint react and endeavour to repair the injury by buttressing the joint. At first there is heat, pain, lame ness. If the joint were then opened and ex amined it would be found hyperaemic and often filled with an excess of syno via. Later in the disease with a continuance of the injury the aforetime smooth cartilage-covered articular surfaces are found roughened and eroded. Then the reaction often proceeds to lay down fibrous tissue in the soft structures surrounding the joint in order to strengthen it, and even stimulates the bone-forming cells (osteoblasts) in the inflamed periosteum to form new bony layers in the joint walls. The chronic inflam matory reaction has for its object the ending of the excessive friction and concussion which are damaging the joint. The consequent pain and lameness usually compel the animal to rest. If made to work by a cruel, ignorant or avaricious owner the damage will increase to such an extent that the sensitive, delicately moulded joint surfaces are destroyed and nature's only resource is to buttress and stiffen the joint so that it becomes fixed or anchylosed, and then, eventually, with enforced absence of friction, callous - but no longer a joint.
Other cases are more immediately unfavour able. Sometimes the infection or primary injury effects the death (necrosis) of a consider able mass of tissue. Following this putrefactive bacteria settle in or upon the dead mass and gangrene supervenes. As a result of the absorp tion of toxic material from the dead putrid tissue septic intoxication occurs and the animal dies from toxcemia or saprcemia.
In other infections, the causal micro-organisms extending in the affected tissue invade the lymphatic vessels or even a vein. In the former case a condition of septic lymphangitis may be set up with production of multiple abscesses along the course of the lymphatic vessels, up to and including the next group of lymphatic glands. Such cases may end favourably by the expulsion of the invading micro-organisms from the abscesses. They may result unfavourably if the glandular reaction is ineffective as a barrier and the bacteria reach the thoracic duct and blood stream. In those cases where micro organisms reach the blood stream, whether through a vein direct or via the lymphatics, the results are always serious. Sometimes the bacteria are simply transported in the blood stream until they reach some set of fine capillaries which filter them out. Such capillaries are found in the lungs, liver, kidneys, and brain, to mention the more important situations, and the bacteria filtered out and held in these organs begin to grow and multiply, setting up new foci of disease, usually in the form of multiple abscesses. This condition is known as pycemia.
In other cases the bacteria find the blood itself a congenial medium for growth and multipli cation. In a very short time the blood swarms with bacteria and a fatal result is inevitable. This condition is known as septiccemia.
Clinical Signs and Symptoms. - As a rule the first indication of inflammation in a part which compels attention on the part of the owner of an animal is impairment of function. A horse gets a sprained tendon and goes lame, or an animal refuses food and salivates, and on inspecting his mouth stomatitis is discovered. A frequent cough, aggravated by feeding, and much increased by pressure over the larynx suggests laryngitis. Detailed examination of the affected part then provides evidence of one or more of the cardinal symptoms, pain, heat, redness, and swelling. In the case of deep seated tissues these signs may be absent, but by means specially adapted to the various organs evidences of local inflammation are to be ob tained. There are, however, in addition certain systemic or general effects of any severe inflam matory reaction. Usually there is more or less fever, with rise of temperature, frequent pulse, and quickened breathing. The appetite may be lessened. The animal may adopt a character istic attitude indicative of pain, sometimes pointing to its localization, and usually adapted to reduce the pain to a minimum. With septic infection and the absorption of toxins special nervous symptoms, drowsiness, stupor or even coma may develop, or in other cases delirium and convulsions. The localizing value of symp toms and the diagnostic value of the signs of inflammation of special parts must be sought for in the sections treating of the diseases of special parts.
Firstly, the"lines of communication"be tween the affected part and the rest of the body must be kept open so that reinforcements of leucocytes and lymph may be brought up, and waste products removed. This points to an attempt to restore and improve the circulation through the blood-vessels of the part. To this end hot fomentations are commonly applied in the early stages, and massage in the later.
Secondly, it may be advisable to flush the part with fresh lymph, in order to provide ample nutriment for repair, and bactericidal fluid for killing off the infecting micro-organisms. This is brought about by such procedure as the old fashioned method of"cupping"or the modern"Bier's treatment"in which by means of an elastic band placed round a limb, for half an hour several times daily, venous congestion and exudation of lymph are promoted. The applica tion of a blister externally in case of sprain, and the use of hypertonic saline solution on dressings applied to a wound, have the same object, namely, to draw out or cause the pouring out of an exudate of fresh lymph.
As part of the procedure to remove the cause an abscess or any collection of pus should be evacuated as soon as it is discovered. Any dead tissue or"sequestrum"in the depth of a wound or at the bottom of a sinus should be removed as early as possible. Antiseptics may be used with advantage thoroughly to disinfect a wound, or abscess cavity, or sinus. Agents which have a specific effect on the supposed causal micro organisms when given by the mouth will be used, if there are such. In cases of Actinomycosis, potassium iodide has undoubted specific action and is a good example of what is meant. To promote leucocytic action various methods have been adopted, notably the internal administra tion of yeast and nucleic acid.
Vaccines, consisting of the dead bodies of bacteria grown in artificial culture from the organisms actually causing the inflammation, are of great value in stimulating the phagocytic activity of the leucocytes and the bactericidal powers of the blood serum. Lastly, the part is put into such a position as to lessen pain, favour the circulation, and promote repair as in the case of a fractured bone or sprained tendon.
For deep-seated inflammations general drug treatment, except the use of agents with proved specific therapeutic properties, is unsatisfactory.
On the other hand, the general condition of the patient may be greatly improved by proper feeding and good nursing in healthy surround ings, especially as regards plenty of fresh air, whilst tonics and stimulants used judiciously may greatly assist in suitable cases.