Reticuloendothelial Apparatus

RETICULOENDOTHELIAL APPARATUS - ENDOTHELIAL APPARATUS, reticuloendothelial system, reticuloendothelium. 1. Historical information. The factual material that later formed the basis of the doctrine of the reticuloendothelial apparatus was collected by many authors for various purposes, starting from the 1870s. Cohnheim, Recklinghausen, and Hoffmann, and especially Ponfik, wishing to trace the paths of substances circulating in the body that serve for cell nutrition, introduced suspensions of various dyes and vermilion into the blood and observed that they are deposited in special cells ('vermilion' cells of Ponfik) scattered in the liver, spleen, bone marrow, lymph nodes, as well as everywhere in connective tissue. In the liver, these cells proved to be identical to the stellate cells of Kupffer. Already in the 1880s, it was proven that the latter also absorb various products of intermediate metabolism (hemosiderin, fat, bile pigments) from the blood and are capable of capturing and destroying red blood cells (Levit). Almost simultaneously, the ability to destroy red blood cells was also attributed to the endothelium and certain cells of the spleen pulp, bone marrow, and lymph nodes (Deny, Henter, Reich, and others.). Vykhovich showed that the same cells represent an important 'regulatory adaptation' with which bacteria entering the blood are removed and neutralized. All these cells were united by Metchnikoff into a group of macrophages that free the body from infectious agents through phagocytosis and, through their activity together with microphages, determine the state of immunity, as well as playing the main role in inflammation. Further accumulation of factual material about the reticuloendothelial apparatus is connected with attempts to study kidney function by introducing lithium carmine into the blood. Ribbert first described the phenomenon of vital staining of cells with carmine and pointed out the significance of this method for clarifying cell function. Goldmann applied the colloidal dyes of the benzidine group (pyrol blue, trypan blue) proposed by Ehrlich for vital staining and showed that they accumulate in a granular form always in certain cells, identical to Ponfik's vermilion cells, as well as to clasmatocytes, adventitial cells, wandering cells at rest, etc., of connective tissue. Schuermann established that the absorption of various colloidal and finely suspended substances by these cells depends not on the chemical nature of these substances, but on their physicochemical state, and is based on the phenomenon of cells adsorbing negatively charged particles. Finally, in 1913, Aschoff and Landau, based on all previous works and on Kiyono's thorough research on vital staining with carmine, put forward the following propositions: in the body there exists a system of reticular and endothelial cells, as well as related connective tissue cells (histiocytes), which constitutes as it were one organ with the characteristic function of absorbing and processing various colloidal and suspended substances circulating in the body's fluids. Many of these substances have important significance in tissue metabolism, hence the name of the reticuloendothelial apparatus as an intermediate metabolism organ. 2. Morphology of the reticuloendothelial apparatus. All cells of the reticuloendothelial apparatus are the closest derivatives of mesenchyme. The latter form the reticular syncytial framework of the hematopoietic organs (bone marrow, spleen, lymph nodes), closely connected with the reticular fibers of their stroma. In addition, this cellular framework forms a single whole with the endothelial cells lining the sinuses of the spleen and lymph nodes and the sinusoids of the bone marrow. Such a syncytial complex is also formed by the Kupffer cells of the liver, lining its capillaries. Depending on the functional state, individual cells of the reticuloendothelial apparatus can become isolated from the syncytial connection with each other and function in the form of free ameboid macrophages. The representatives of the reticuloendothelial apparatus cells in connective tissue are the so-called histiocytes (wandering cells at rest) scattered throughout it. They represent the closest derivatives of both sedentary and 'primary wandering cells' of embryonic mesenchyme that remain in some quantity in an undifferentiated state also in the adult organism. Particularly large accumulations of histiocytes are found along the walls of capillaries (adventitial cells). Histiocytes are very numerous in the omentum tissue, where they form entire accumulations laid in the loops of the syncytial network of mesenchymal cells (so-called milk spots). Free ameboid macrophages, derivatives of histiocytes, are constantly found in the abdominal cavity (many authors previously derived them from the mesothelium of the peritoneum). In general, the cells of the reticuloendothelial apparatus constantly undergo various stages of transformation from indifferent mesenchymal cells that do not have the ability to accumulate vital dyes to free macrophages and therefore do not differ by any quite characteristic constant morphological features. The belonging of certain cells to the reticuloendothelial apparatus is determined mainly by their functional feature - the ability to absorb to a much greater extent than other cells colloidal vital dyes and particles of various suspensions. 3. The general research methodology of the reticuloendothelial apparatus is based mainly on its property of absorbing various substances artificially introduced into the blood. The Adler and Reimann method consists in introducing a 1% solution of congo red into the blood with subsequent (after 4 minutes and 1 hour) colorimetric determination of the dye content in the serum. The percentage ratio of the amount of dye in the second portion of serum to the amount in the first ('congo red index') in humans is 50-70; in septic processes, circulatory disorders, liver diseases, after splenectomy, the congo red index often rises to 80-100. Instead of congo red, other harmless colloidal dyes can also be used, for example tetrachlorophenolphthalein. The test with congo red is inaccurate, as this dye quite easily diffuses through capillary walls and impregnates the intermediate substance and fibers of connective tissue, especially elastic ones. In general amyloidosis, it is not applicable due to the pronounced adsorptive ability of amyloid towards congo red. The Sachs and Donat test is based on determining the rate of disappearance from the blood of particles of a fine emulsion of olive oil ('hemokoniol') after its introduction into a vein. This method is inaccurate, as some of the introduced emulsion precipitates from the suspended state in capillaries, and another part is destroyed by blood lipase. More accurate results are apparently obtained by introducing colloidal iron compounds into the blood, for example Ferrum oxydatum saccharatum, with subsequent determination at different time intervals of the iron content in the serum (Leites and Ryabov). Finally, attempts were made to judge the function of the reticuloendothelial apparatus by the amount of urobilin in the blood. Urobilin, being absorbed into the blood from the intestine, is captured by the cells of the reticuloendothelial apparatus, and therefore its content in the blood partly characterizes the functional state of the reticuloendothelial apparatus. The experimental study of the function of the reticuloendothelial apparatus is based mainly on its exclusion by 'blockade' (see below) with any colloidal substances or suspensions, as well as on the removal of the spleen as an organ particularly rich in cells of the reticuloendothelial apparatus. 4. The general functional significance of the reticuloendothelial apparatus is much more extensive than just the removal from the blood and lymph of all sorts of foreign or formed in the process of tissue metabolism colloidal and larger particles. According to modern concepts, an exchange of various substances constantly occurs between the cells of the reticuloendothelial apparatus and the body's fluids. Particles of some substances are absorbed from the blood or lymph by elements of the reticuloendothelial apparatus, other substances, on the contrary, are secreted by them into the body's fluids. Thanks to this, the relative constancy of the colloidal and corpuscular composition of the body's fluids is maintained and the normal course of life processes is ensured. On the other hand, the various substances absorbed by the cells of the reticuloendothelial apparatus undergo processing in them and then enter the parenchymal cells of organs in a new form. Although many even basic features of this process are still unknown, the presence of the indicated function fully justifies the concept of the reticuloendothelial apparatus as the most important organ of intermediate metabolism. The absorption, processing, neutralization, and excretion of various substances by the cells of the reticuloendothelial apparatus occur especially energetically. Hence the designation used by many for the reticuloendothelial system as a system of 'active' mesenchyme, although under this name not only the elements of the reticuloendothelial apparatus in the proper sense are often united, but together with them other cells of connective tissue, as well as the endothelium of blood vessels in general. 5. Division of the reticuloendothelial apparatus. Based on the expressiveness of the phenomena of absorption of colloidal substances and suspensions, Aschoff distinguishes the reticuloendothelial apparatus in the proper, narrower sense, which includes endothelial and reticular cells of the liver, spleen, bone marrow, and lymph nodes, and the reticuloendothelial apparatus in the broad sense of the word; the latter includes all histiocytes of connective tissue, which have less absorptive capacity than the cells of the proper reticuloendothelial apparatus of internal organs. Such a division is, however, purely conditional.

The absorptive capacity of the cells of the R.-e. a. depends to a large extent on the method of introduction of various substances and on their properties. Thus, with subcutaneous administration of colloidal dyes and suspensions, they are first and in particularly large quantities accumulated in the local connective tissue histiocytes and in the regional lymph nodes. Even with intravenous administration of vital dyes, many histiocytes show no less ability to absorb them than the cells of the R.-e. a. in the proper sense (e.g., histiocytes of the stroma of the heart, seminal gland, etc.). A more rational classification of the R.-e. a. is in connection with its main function of maintaining the constancy of the composition of the body's fluid media and depending on which of these media a particular part of the R.-e. a. is functionally-topographically related to. Therefore, one can distinguish the R.-e. system of the blood, otherwise called the hepatolienal system, which also includes the reticulo-endothelium of the bone marrow (the so-called "coastal" blood cells), the R.-e. system of the lymph (lymph nodes) and the R.-e. system of the tissue lymph (histiocytes of connective tissue). 6. The function of absorption (Speicherung) by the cells of the R.-e. a. of various colloidal substances and suspensions is considered particularly characteristic of the R.-e. a., and on its basis the belonging of one or another cells to the R.-e. a. is judged. Many believe that it is essentially identical with phagocytosis and based on the same phenomena of surface activity and adsorption. In general, despite the large number of various theories trying to explain the phenomenon of absorption and accumulation by cells of colloidal substances and suspensions, the mechanism of this phenomenon remains unexplained. All these theories are essentially identical with the theories of vital staining. Particularly characteristic of the absorption process (Speicherung) is the accumulation in the protoplasm of the cells of the R.-e. a. of one or another substances in a granular form, and these grains are not connected with any pre-existing structural elements of the protoplasm. However, recently the importance of the Golgi reticular apparatus in this process is being emphasized, in the area of which the grains of the introduced vital dye first appear. The ability to accumulate colloidal substances and suspensions in a granular form depends on the properties of the R.-e. a. cells themselves, on the conditions of delivery to them of one or another substance, on the properties of the latter and finally on the properties of the liquid medium washing the cells. A. The ability of the R.-e. a. cells themselves to accumulate substances in a granular form is closely related to the normal life activity of the cells and is disrupted in any dystrophic phenomena in the cells. Dead cells and their nuclei are only diffusely impregnated with colloidal dyes. Furthermore, the absorptive capacity of the R.-e. a. depends on the greater or lesser content in its cells of previously captured substances, i.e., on the degree of their "blockade" (see below). A number of substances, especially of a protein nature, at a certain dosage sharply increases the absorptive capacity of the R.-e. a. Finally, this capacity depends on the stage of development of the R.-e. a. cells and increases as they transform from indifferent mesenchymal cells into free ameboid macrophages. The absorptive capacity of individual groups of R.-e. a. cells, all other conditions being equal, is not quite the same: for example, it is particularly strongly inherent in Kupfer's cells of the liver, to a lesser degree in the R.-e. a. of the spleen, and further in the spleen itself, reticular cells accumulate colloidal substances and suspensions usually in somewhat larger quantities than the sinus endothelium. The absorptive capacity of the same parts of the R.-e. a. in different species of animals and at different ages is also expressed to a varying degree. However, in this respect there are still very few observations. Individual parts of the R.-e. a. can replace each other compensatory: thus, after splenectomy, foci of "splenic" tissue develop in the liver, where increased absorption of colloidal substances and suspensions occurs. The function of absorption in the R.-e. a. t. xxviii.

RETICULO-ENDOTHELIAL APPARATUS

The absorption of various substances by the reticuloendothelial apparatus has the following additional peculiarities: it manifests extremely rapidly after the introduction of one or another substance into the blood; for example, after the introduction of a suspension of India ink, the latter is detected in Kupffer cells of the liver within just a few minutes. Furthermore, the absorptive function of the reticuloendothelial apparatus is characterized by very high sensitivity: the presence of foreign colloids in the blood, even in minimal concentrations (e.g., 1:10,000 for trypan blue), is sufficient for their granular deposits to appear in some cells of the reticuloendothelial apparatus after a short time. The absorptive capacity of the reticuloendothelial apparatus is extremely great: it is possible to introduce enormous quantities of indifferent suspensions (e.g., India ink) into animals for many months, and all of them are invariably absorbed by the cells of the reticuloendothelial apparatus, which at the same time undergo marked hypertrophy and increase in number. In the same cells of the reticuloendothelial apparatus, numerous grains of the most diverse absorbed substances can simultaneously be present (for example, introduced colloidal dye, hemosiderin, phagocytized particles of other disintegrated cells, etc.). Just as rapidly as the cells of the reticuloendothelial apparatus accumulate particles of various substances, they subsequently release them just as slowly. Complete cleansing of the reticuloendothelial apparatus from introduced colloidal substances or suspensions occurs only after several months. This occurs in such a way that cells of the reticuloendothelial apparatus, heavily loaded with grains of introduced substances, partly detach from the walls of capillaries and are carried by the blood current to the lungs, where they are destroyed; partly such cells are also destroyed in situ in the organ where they are located, or sometimes they pass into the connective tissue stroma of the organ (e.g., the liver), where they remain for a very long time. _f Finally, the reverse excretion of absorbed substances by cells into the blood or lymph is also possible, from which these substances are partly again extracted by other cells of the reticuloendothelial apparatus, and partly are removed through the excretory organs. The ability to absorb and accumulate various colloids in granular form is not an exclusive property of the cells of the reticuloendothelial apparatus. Cells of certain organs, e.g., the liver and kidneys, through which the excretion of colloids introduced into the body occurs, possess the same ability. Also other cells, e.g., fibroblasts, certain epithelia, etc., when the body is heavily loaded with colloids, accumulate them in the form of grains. However, among all cells (except for the epithelium of the main segments of the renal tubules), this ability is expressed in the elements of the reticuloendothelial apparatus to a particularly marked degree. Moreover, the grains of introduced substances in the cells of the reticuloendothelial apparatus themselves have some rather characteristic properties: they are coarse, angular, often consist of conglomerates of smaller grains connected by a protein substance produced by the cell ("crinoma" of Khlopin). B. The conditions of delivery of various substances to the cells of the reticuloendothelial apparatus are strongly reflected in the absorptive function. Thus, coarse suspensions introduced into the blood accumulate only in the reticuloendothelial apparatus of internal organs and are not deposited at all in the reticuloendothelial apparatus of lymph nodes and in histiocytes of connective tissue, because particles of suspensions do not penetrate through the walls of blood capillaries. The more intense the blood circulation in a particular area, the more pronounced, in general, is the accumulation here in the cells of the reticuloendothelial apparatus of introduced substances. Thus, this process is greatly increased under artificially induced arterial hyperemia. The reticuloendothelial apparatus in certain organs supplied most abundantly with blood accumulates introduced colloidal substances in particularly large quantities (e.g., heart muscle, pregnant uterus). Due to the uneven and simultaneous filling of different parts of the capillary network in organs with blood, the absorption of colloidal substances in the early stages often has a focal character (e.g., in the spleen, in the liver). C. The dependence of the absorptive function of the cells of the reticuloendothelial apparatus on the properties of the absorbed substances. Absorption affects negatively charged particles of very diverse sizes, ranging from small particles of various colloids to large particles of suspensions the size of erythrocytes. Many organic colloids that do not possess a charge become negatively charged in the weakly alkaline media of the body and are therefore also absorbed in the reticuloendothelial apparatus. In general, very diverse conditions (presence of electrolytes, concentration, etc.) influence the charging of colloids, and therefore it is very difficult to predict whether a given colloid will be absorbed by the cells of the reticuloendothelial apparatus. The ability to absorb only negatively charged particles is explained by some authors as being due to the positive charging of the cells of the reticuloendothelial apparatus. When such particles come into contact with elements of the reticuloendothelial apparatus, discharge of the particles and their precipitation from the suspended state occurs. D. The dependence of the absorptive function on the properties of the liquid medium surrounding the cell is best demonstrated by the fact that in elements of the reticuloendothelial apparatus of isolated organs, washed with isotonic and isoionic fluid, absorption of colloidal dyes hardly occurs. Somewhat better, although also in very small amounts, particles of coarse suspensions are absorbed under these conditions. This fact is apparently explained by the absence of colloidal substances in the washing fluid. It is assumed that particles of colloids are perceived by the cells of the reticuloendothelial apparatus in complex combination with blood proteins. The absence of proteins in the washing fluid is apparently the reason for the very limited absorptive capacity of the cells of the reticuloendothelial apparatus of isolated organs, although many other functions of the latter remain preserved. Histiocytes of connective tissue, which do not absorb trypan blue when kept in Ringer's solution, are nevertheless not dead: when transferred to blood plasma, they exhibit growth phenomena and again acquire the ability to absorb dye. 7. Blockade of the reticuloendothelial apparatus. The question of the blockade of the reticuloendothelial apparatus arose as a result of experiments with the simultaneous absorption of several different colloids by cells. When two different colloidal dyes are introduced, mixing of the latter in the cells and the appearance of grains of intermediate shade are never observed. Successively introduced colloidal substances are deposited mainly in different cells of the reticuloendothelial apparatus. This is explained mainly by the fact that the first of the introduced substances blocks part of the cells of the reticuloendothelial apparatus, namely the most functionally active ones, as a result of which the ability to absorb successively introduced substances is reduced. However, it is impossible to destroy the absorptive capacity of all or at least a significant number of cells of the reticuloendothelial apparatus by means of blockade. Under the influence of partial blockade, the ability of cells of the reticuloendothelial apparatus to absorb various substances is often even enhanced. However, local blockade of individual cells of the reticuloendothelial apparatus is quite possible. Such macrophage cells, overloaded with the blocking substance, no longer absorb other successively introduced colloids. There are indications that besides the mechanical influence of blockade in the sense of loading the cells of the reticuloendothelial apparatus, toxic effects on the cells by various substances deposited in them are also of great importance. The most complete and prolonged blockade of the reticuloendothelial apparatus is achieved by the introduction of colloidal metals, in particular colloidal gold. Despite the impossibility of achieving complete blockade of the entire reticuloendothelial apparatus, blockade is still used as a method for weakening the function of the reticuloendothelial apparatus, especially in studying the role of the reticuloendothelial apparatus in intermediate metabolism and in phenomena of immunity. However, the application of the blockade method without proper consideration of the amount of substance introduced, the time and place of its introduction, as well as its nature, has been the cause of major disagreements in the conclusions of individual researchers. To obtain a more or less significant blockade of the reticuloendothelial apparatus, it is best to perform repeated massive injections of blocking substances in a short time. If injections are made in small portions over a longer period, the cells of the reticuloendothelial apparatus partly have time to hypertrophy and regenerate, and partly to free themselves from absorbed particles, and instead of weakening, an even strengthening of the functions of the reticuloendothelial apparatus may result. Besides the phenomenon of "self-cleansing" of the reticuloendothelial apparatus from substances absorbed in its cells, it is also necessary to consider in blockade experiments the possibility of their "deblocade". By this term is understood such a phenomenon when the blocking substance passes back from the cells into the liquid media of the body under the influence of the absorption of another successively introduced substance. In studying the effect of blockade, little account is also taken of the fact that many blocking substances are deposited not only in the cells of the reticuloendothelial apparatus, but also in the parenchyma of organs (especially the liver and kidneys) and can exert a harmful effect on it, both mechanical and toxic. Very interesting are the recent attempts to find substances that act selectively in a toxic manner on the reticuloendothelial apparatus (introduction of bacterial bodies, cytotoxic serum). 8. Cells of the reticuloendothelial apparatus in the blood, their relation to monocytes.

After significant loading with blocking substances, a constant detachment of individual cells of the R.-e. a. from the capillary walls and their appearance in the form of large macrophages filled with granular inclusions in the blood is always observed, especially in the large veins draining blood from the abdominal cavity (v. porta, v. hepatica). Such blood histiocytes-macrophages get stuck in the capillaries of the lungs, where they are destroyed, however, some of them can pass into peripheral vessels. According to the opinion of most authors, the transition of cells of the R.-e. a. into the blood occurs constantly and in normal conditions, and such cells appear in the form of monocytes. However, this question still causes some disagreements. Part of the authors asserts that only some monocytes are of reticulo-endothelial origin, while others originate from lymphocytes or even belong to myeloid forms. In many diseases, the transition of cells of the R.-e. a. into the blood is sharply intensified, and we have phenomena of monocytosis and histiocytosis even in the peripheral blood. This includes primarily some chronic infections and sepses, in which there is constant irritation of the R.-e. a. by protein, especially bacterial antigens (endocarditis lenta, malaria, typhus and typhoid fever, kala-azar, mononucleosis angina). Some authors believe that macrophages and blood monocytes can originate not only from the R.-e. a., but also from the endothelium of vessels in general, especially under sharp and prolonged exposure to bacterial antigens. Often in septic processes, monocytes circulating in large quantities in the blood form so-called monocyte thrombi on the vessel walls. Carried by the blood current and stopping somewhere in the capillaries, monocytes and macrophages can pass into tissues, for example participating in local inflammatory phenomena. 9. The relationship of the R.-e. a. to hematopoiesis. The participation of cells of the R.-e. a. in hematopoiesis is admitted by a number of authors due to the genetic closeness of these cells to elements of poorly differentiated embryonic mesenchyme. Under the action of pathogenic irritants in experimental conditions, a direct transition of cells of the R.-e. a. (and even of endothelium in general) into young cells of the myeloid series and into erythroblasts has been described, though more often through an intermediate stage of hemocytoblast. This process was attributed particularly important significance in heteroplastic extramedullary hematopoiesis (for example, in anemias, leukemias). However, most authors deny the possibility of the direct formation of cells of the myeloid series and erythroblasts from the R.-e. a. In their view, in this process during extramedullary hematopoiesis, hemocytoblasts brought from the bone marrow participate, or cells of undifferentiated mesenchyme, constantly preserved in some quantity even in the adult organism, especially along the course of vessels. These cells more often differentiate in the direction of cells of the R.-e. a., monocytes and macrophages, but under pathological conditions can also differentiate in the direction of cells of the myeloid and erythrocytic series. 10. The significance of the R.-e. a. in intermediate metabolism. A. Significance in lipid metabolism. The frequent finding of lipid inclusions in cells of the R.-e. a. and observations on the sharp accumulation of these inclusions in them during experimental loading of the organism with lipids served as the basis for recognizing the important role of the R.-e. a. in lipid metabolism. Particularly large amounts of fat substances are found in cells of the R.-e. a. in general disturbances of lipid metabolism accompanied by lipoidemia, for example in diabetes mellitus. Sometimes in this disease abundant deposits of lipids (especially doubly refracting compounds and mixtures of cholesterol) are found in the tissues (so-called diabetic xanthoma). Lipids are absorbed by histiocytes, which transform into large, foamy, so-called xanthoma cells containing numerous droplets of cholesterol fats. Sometimes especially many such cells accumulate in the spleen, which sharply increases in volume (diabetic splenomegaly). The formation of local deposits of lipids in connective tissue and accumulations of xanthoma cells on the basis of a general disturbance of lipid metabolism is called infiltrative xanthoma (symptomatic xanthoma, xanthelasma) in contrast to resorptive xanthoma (pseudoxanthoma), which forms during local resorption of lipids, for example from disintegrating tissues. In most cases of xanthelasma formation there is hypercholesterolemia as a manifestation of a general disturbance of lipid metabolism (in diabetes, chronic jaundice, sometimes in nephritis). Only rarely are cases of essential xanthoma without hypercholesterolemia encountered. They are explained by a primary disturbance of lipid metabolism in the cells of the R.-e. a. themselves. A particularly severe systemic lipid infiltration of cells of the R.-e. a. is characteristic of Niemann-Pick disease (see Niemann-Pick disease) and of Christian disease. The participation of the R.-e. a. in lipid metabolism, in addition to morphological data, is also proven by the appearance of hypercholesterolemia after removal of the spleen. Data on the effect of blockade of the R.-e. a. on the content of lipids in the blood are contradictory. In general, only the fact of absorption of lipids by the R.-e. a. has been firmly established to this day, but very little is known about the further transformations of lipids captured by the cells. The results of histochemical research in this area are very unreliable. The view of some French authors that lipids are produced by cells of the R.-e. a. (especially in the spleen) has in general not met with approval. B. Significance in protein metabolism. Information in this respect is very scarce due to the difficulty of histochemical detection of proteins and is based mainly on indirect data, for example on the swelling and hyperplasia of cells of the R.-e. a. after parenteral administration of proteins ('activation' of the R.-e. a.), their capture of Hb, some metalloproteins, absorption and destruction by them of particles of disintegrating cells, etc. Further, it is pointed out that deamination of amino acids occurs more weakly in animals after blockade of the R.-e. a. Finally, the formation of some specific protein substances, such as amyloid, is also associated with the function of the R.-e. a. In the occurrence of amyloid, according to existing views, destruction of proteins occurs in cells of the R.-e. a., reaching the formation of easily precipitable intermediate products. An example of a systemic lesion of the R.-e. a. on the basis of a general disturbance of one type of nitrogen metabolism is the deposition of cerebrosides, in particular kephalin (sometimes in mixture with lipids) in its cells in Gaucher's disease.-C. The significance of the R.-e. a. in carbohydrate metabolism is recognized by some authors mainly on the basis of observations on glycemia during blockade. The increase in glucose content in the blood found at this time has not however been confirmed by other researchers, for which reason the question must still be considered open.-D. The significance of the R.-e. a. in water metabolism has been studied very little. In this respect the most convincing are indications of water retention in the body occurring after blockade of the R.-e. apparatus. E. The significance of the R.-e. a. in the process of destruction of the formed elements of blood and in iron metabolism. Phagocytosis of erythrocytes with their subsequent destruction and the formation of grains of hemosiderin constantly occurs in cells of the R.-e. a., especially in the spleen, and in many pathological processes reaches a very sharp degree. In this process erythrocytes are destroyed both previously damaged in the blood itself (for example in hemolysis, burns, Weil's disease, malaria) and those appearing completely normal. However, a number of authors hold the opinion that erythrophagocytosis is always preceded by damage to erythrocytes by hemolytic substances also secreted by cells of the R.-e. a. Finally, in extracellular hemolysis, the Hb released also accumulates in cells of the R.-e. a. and is destroyed here, forming deposits of hemosiderin. In general, the destruction of erythrocytes can occur by each of the indicated methods (intracellularly, extracellularly and in a mixed manner) depending on the nature and strength of action of the hemolytic poison, the species and age of the animal, the functional state of the R.-e. a., etc. The R.-e. a. of the liver and especially the spleen have predominant significance in this process. After splenectomy the process of destruction of erythrocytes in Kupffer cells of the liver, and partly in other parts of the R.-e. a., sharply intensifies. The number of erythrocytes in the peripheral blood increases after splenectomy. The osmotic resistance of erythrocytes increases after removal of the spleen. Finally, there are indications that by means of blockade it is possible to significantly reduce the ability of cells of the R.-e. a. to destroy erythrocytes and accumulate hemosiderin. At the same time, various changes occur in the morphological picture of the red blood, and phenomena of irritation of the erythroblastic function of the bone marrow alternate with a picture sometimes very sharply expressed oligocythemia. An intensification of erythrophagocytosis by cells of the R.-e. a. is observed in chronic starvation, in many infectious diseases (sepsis, typhoid fever, endocarditis lenta), accompanied by an intensification of the function of the R.-e. a. The phenomenon of destruction of erythrocytes and deposition of hemosiderin in cells of the R.-e. a. is very sharply expressed in pernicious anemia.

However, the histological findings in pernicious anemia (the abundance of iron in Kupffer's cells with the relative poverty of the spleen in it) do not quite correspond to the view that this form is due only to the excessive intensification of the process of erythrocyte destruction in the R.-e. a. The hemolytic function of the R.-e. a. is also sharply enhanced in congenital hemolyic jaundice, to which Eppinger ascribes important significance in the pathogenesis of this disease (hence the operation of splenectomy proposed by him). In acquired infectious-toxic jaundice, the hemolytic function of the R.-e. a. is also enhanced, although not to such a significant degree. The process of destruction of erythrocytes and the deposition of iron-containing pigment in the R.-e. a. reaches its greatest development in hemochromatosis, although the role of the primary increase in the function of the R.-e. a. in this disease remains still controversial. Some consider the primary decrease in the erythroclastic function of the R.-e. a. to be characteristic of polycythemia vera. The participation of the hemolytic function of the R.-e. a. in the origin of all the mentioned diseases is judged mainly by the expressiveness of the phenomena of erythrophagia and by the content of hemosiderin in the cells of the R.-e. a. However, the amount of iron found microscopically in organs does not always correspond to the amount determined chemically. Furthermore, even in cases of sharply expressed destruction of erythrocytes, both a primary increase in the function of the R.-e. a. and a subsequent 'passive' loading of it with products of hemolysis are possible. It is very difficult to distinguish these two processes from each other. Chemical studies of the iron content in different organs of the R.-e. a. and especially the finding of large amounts of it in the spleen indirectly confirm the significance of the R.-e. a. in the process of destruction of red blood. In this respect, the sharp increase in the iron content in the spleen in diseases associated with increased destruction of erythrocytes, for example in pernicious anemia, is especially important. The significance of the R.-e. a. in the destruction of red blood is closely connected with its role in the intermediate metabolism of iron. The R.-e. a. is, as it were, a huge depot of iron in the body, retaining this element valuable for respiratory function. After splenectomy, the amount of Fe excreted from the body sharply increases. The iron deposited in the cells of the R.-e. a. gradually passes again into the general bloodstream and is used in the bone marrow in the production of erythrocytes. Thus, a constant circulation of iron occurs between the R.-e. a. and the bone marrow, regulated, as some believe, by hormonal influences from the spleen. The attempts of various authors to influence the process of destruction of erythrocytes and the metabolism of iron by blocking the R.-e. a. have led to very contradictory results, which is probably explained by the shortcomings of the blocking method itself (see above). Along with iron resulting from hemolysis, iron of exogenous origin is also deposited in the R.-e. a. Experimentally, it is possible to cause an enormous accumulation of the latter in the R.-e. a. and especially in the spleen by the introduction of colloidal iron preparations. There are quite a few indications that the destruction of leukocytes also occurs in the R.-e. a., especially in the spleen and in the Kupffer's cells of the liver. Leukocytes artificially introduced into the blood, taken from an abscess, are captured and destroyed in huge quantities by the cells of the R.-e. a. After thyroidectomy, the absorption of leukocytes by macrophages sharply weakens, which speaks in favor of the dependence of this process on hormonal influences. The significance of the R.-e. a. in the destruction of blood plates follows mainly from the change in their quantity in the blood after blocking the R.-e. a. and splenectomy (an increase sometimes by 50%). After splenectomy, the number of plates in the blood returns to normal only after 2-3 months, while with blocking it already happens after several days. Plates are apparently destroyed mainly in the spleen by their phagocytosis by the cells of the R.-e. a. On the basis of this fact, removal of the spleen has been proposed for essential thrombocytopenia accompanied by splenomegaly and bleeding. 11. The significance of the R.-e. a. in the formation of bile pigments and in the pathogenesis of jaundice. The amount of bilirubin formed in the body depends on the intensity of erythrocyte destruction and the splitting of hematin. Since the erythroclastic function of the R.-e. a. has been proven, it is already a priori probable that this system also participates in the production of bile pigments, which fully agrees with the old views of Virchow on the possibility of bilirubin formation not only in the liver, but also everywhere in tissues during the destruction of erythrocytes. However, later the hematogenous formation of bilirubin was rejected on the basis of the results of experiments by Minkowski and Naunin with the removal of the liver in birds. In such animals, in contrast to the controls, poisoning with hemolytic poisons (arsine and toluylenediamine) did not lead to the formation of jaundice. These experiments were later interpreted by Aschoff and McNeal in the sense that removal of the liver in birds is equivalent to the exclusion of a very important department of the R.-e. a., in which (in Kupffer's cells) in birds the destruction of erythrocytes and the production of bilirubin mainly occur. Furthermore, experiments by Lepene showed that blocking the R.-e. a. with collargol significantly weakens the production of bilirubin and delays the appearance of jaundice caused by hemolytic poisons. Similar results were also obtained by Eppinger when blocking the R.-e. a. with colloidal iron oxide. All these data allowed Aschoff to express the view of the production of bilirubin by the R.-e. a. and the existence of reticuloendothelial ('extracellular hepatic') jaundice. However, this theory met with sharp objections and the main proof of it—the absence of hemolytic jaundice when blocking the R.-e. a.—was not confirmed by some later researchers (Rosenthal and his collaborators). Furthermore, according to the observations of Billing and Isaac, the action of hemolysins is not weakened by blocking, therefore the formation of bile pigments can also occur outside the R.-e. a. Finally, morphological observations (Kanner, Lubarsch) do not give clear indications of the production of bilirubin in the cells of the R.-e. a. The question entered a new phase after the publication by Mann and Magath of the method of liver removal in dogs and after the development by H van den Berg of an exact quantitative method for determining bile pigments in the blood. Experiments with liver removal in dogs and causing hemolysis in them finally confirmed the possibility of extracellular formation of bile pigments, although under these conditions their formation occurs in small amounts. The latter is easily explainable by the severe condition of the animals and their relatively short survival after the operation. The van den Berg reaction made it possible to distinguish in the blood the bile pigments formed in the R.-e. a. by hemolysis from the pigments passing into the blood in stagnant jaundice (indirect and direct reaction). However, parallel morphological studies and determinations of bilirubin in the blood showed that hemolytic jaundice in the early stages can pass into stagnant jaundice due to the formation of 'bile thrombi' in the small hepatic ducts (Kodama, Makino). Thus, none of the methods used led to completely indisputable proof of the existence of reticuloendothelial jaundice. However, summarizing all the data obtained on this issue, and especially taking into account the possibility of bile pigment formation after liver removal, it is necessary to recognize the very fact of bilirubin production in the cells of the R.-e. a. From this, one can also admit the important significance of the R.-e. a. in the development of hemolytic jaundice, especially some of its forms (constitutional hemolytic jaundice, jaundice of newborns, jaundice in Weil's disease). Recently, some authors are taking a middle position in the question of bilirubin formation and the genesis of hemolytic jaundice, considering that the initial stage of the process—hemolysis and the detachment of iron from Hb—proceeds with the participation of the R.-e. a., while the further stages are connected with the functions mainly of hepatic cells. 12. The reticuloendothelial system and internal secretion. This question is developed mainly from the point of view of the influence of various secretions on the absorptive capacity of the R.-e. a., and the data obtained are extremely contradictory. The influence of thyroidectomy, removal of the pancreas and other glands was also studied, but in this respect the results of experiments turned out to be little convincing. According to some authors, the sometimes observed fluctuations in the amount of absorbed substances in the R.-e. a. under the influence of introduced hormones depend less on the action of the latter on the cells of the R.-e. a. than on the occurring changes in vascular tone and permeability of vessels. 13. The significance of the R.-e. a. in immunity and infection is based first of all on the absorption by the cells of the system of various microbes that have entered the body in one way or another. All authors emphasize the remarkable speed of capture and destruction of bacteria in the R.-e. a., as well as its ability to retain huge amounts of microbes.

The main participation in this process when microbes are introduced into the blood is taken by the reticuloendothelial apparatus of the liver, spleen, and bone marrow; however, it is possible that in some cases similar functions are also manifested by other endothelial cells, for example, in peripheral vessels. After splenectomy, the process of removing bacteria from the blood sharply slows down. The same applies to foreign erythrocytes introduced into the blood. The effect of blocking the reticuloendothelial apparatus apparently does not manifest itself so clearly in this regard, and the data on this point are contradictory. Cells of the reticuloendothelial apparatus, having absorbed a large number of microbes, are to a certain degree blocked and less capable of perceiving other suspended substances and colloids. The absorption of bacteria by cells of the reticuloendothelial apparatus and the disappearance of microbes from the blood occurs much more quickly and completely in immunized animals. Blocking of the reticuloendothelial apparatus in immunized animals causes a more pronounced delay in the disappearance of pathogens from the blood than in non-immunized animals. This phenomenon is observed only in acquired active immunity. In addition to phagocytosis, the parenteral introduction of bacteria, as well as various protein antigens, also causes other phenomena of irritation (activation) of cells of the reticuloendothelial apparatus, expressed by their swelling and proliferation. Some authors extend the concept of these processes to other cells of mesenchymal origin, especially to the entire vascular endothelium, and speak of reactions of active mesenchyme as a whole; however, in these reactions the main role undoubtedly belongs to the reticuloendothelial apparatus. The above-mentioned general reactive changes of the reticuloendothelial apparatus are non-specific and are expressed, albeit to varying degrees, upon the parenteral introduction of various protein bodies of foreign origin. Modern conceptions of the essence of immunity assign a very important role to the phenomena of phagocytosis of pathogens by cells of the reticuloendothelial apparatus and the activation of the latter. Indeed, a number of data indicate that after splenectomy or blocking of the reticuloendothelial apparatus, natural immunity sharply decreases (especially in relation to protozoan and spirochete infections). The similar effect of splenectomy and blocking is even more clearly manifested in artificial active immunity. In contrast to this, sensitivity to toxins apparently does not depend on the effect of blocking the reticuloendothelial apparatus or splenectomy. The activation of the reticuloendothelial apparatus upon the introduction of antigens is expressed not only by phenomena of hypertrophy and phagocytosis, but also by the production of various antibodies. The connection between antibody production and the function of the reticuloendothelial apparatus, put forward by Mechnikov in relation to macrophages, has now been proven both by experiments with blocking and by splenectomy. The delay in the formation of hemolysins and agglutinins is particularly evident after these effects. However, the methodology of blocking and the timing of research after blocking or splenectomy have a great influence on the results of these experiments. Insufficient or slow blocking can at certain times give completely opposite results, since phenomena of weakening and strengthening of the function of the reticuloendothelial apparatus replace each other, which explains some of the existing contradictions on this issue. Important evidence in favor of antibody production by cells of the reticuloendothelial apparatus has also been obtained by the method of tissue cultures. Recognition of the primary importance of the reticuloendothelial apparatus in the process of immunity allows one to unite the cellular and humoral theories of immunity into a single whole, reducing them to the manifestation of the functional activity of the same cellular system. 14. Significance of the reticuloendothelial apparatus in anaphylaxis and protein therapy. According to some data, blocking of the reticuloendothelial apparatus and splenectomy prevent the development of anaphylactic phenomena in sensitized animals. However, the choice of appropriate timing for sensitization, blocking (or splenectomy), and the provocative injection is of great importance. Thus, according to available data, splenectomy performed shortly before sensitization prevents the onset of shock, while performed after sensitization and before the provocative injection has no effect. Finally, according to the latest observations, splenectomy and blocking can also prevent the development of local anaphylactic reaction, expressed as hyperergic inflammation. The phenomenon of activation of the reticuloendothelial apparatus upon the parenteral introduction of protein antigens allows one to attribute to this system an important role in protein therapy. Weichardt's concepts about the activation of cellular protoplasm by foreign proteins refer primarily to the cells of the reticuloendothelial apparatus. However, it should not be forgotten that the parenteral introduction of protein causes many different reactions, not only cellular, but also humoral and neuro-hormonal in nature. What share of the effect of protein therapy in this complex of phenomena is due to the activation of the reticuloendothelial apparatus remains unclear. 15. Significance of the reticuloendothelial apparatus in chemotherapy. Many chemotherapeutic agents (especially salvarsan and its derivatives) after being introduced into the blood are quite quickly deposited in the reticuloendothelial apparatus, causing either its activation or blockade. Therefore, the chemotherapeutic effect depends not only on the interaction between the drug and the pathogen, but also on the participation of the reticuloendothelial apparatus in the process. This position has been proven by many studies, mainly with blocking of the reticuloendothelial apparatus. The latter, at certain stages, sharply reduces the chemotherapeutic effect even of the most vigorously acting agents in this regard. Although the very fact of the necessary participation of the reticuloendothelial apparatus in the action of chemotherapeutic substances does not cause doubt, however, explanations of the mechanism of this phenomenon have not yet been given. There are assumptions that chemotherapeutic substances pass into a particularly active form in the cells of the reticuloendothelial apparatus, that they accumulate in them, as in a depot, and then, constantly being released from them, exert a killing effect on pathogens, etc. The question is further complicated by the fact that the chemotherapeutic effect of various substances does not go parallel with their ability to be deposited in the reticuloendothelial apparatus, and that most of these substances, after deposition in the reticuloendothelial apparatus, have no effect on pathogens. The use of large doses of chemotherapeutic substances eliminates the weakening effect of blocking and splenectomy on the therapeutic effect. 16. Participation of the reticuloendothelial apparatus in inflammatory processes. Among the cellular forms participating in inflammation, the reticuloendothelial apparatus includes polyblasts or macrophages, possessing phagocytic function and the ability to accumulate grains of colloidal dyes in the protoplasm. Most authors recognize the dual origin of these cells: from pre-existing histiocytes of connective tissue and from mononuclear cells migrating from the blood vessels. Their origin from blood lymphocytes is disputed by many. Macrophages of inflammatory foci are particularly functionally active cells of the reticuloendothelial apparatus. They energetically absorb and digest on the field of inflammation various necrotic tissue elements and exudates, pathogens of infection, etc., while at the same time being carriers of various enzymes and antibodies. Therefore, some consider their function especially important in inflammation, regarding the latter as a process of intracellular digestion in connective tissue. In any case, the activation of local and the influx of wandering (mononuclear) cells of the reticuloendothelial apparatus is a very essential component of the inflammatory process. At the end of the inflammatory process, part of the macrophages is destroyed, part passes into a resting stage and, in the form of histiocytes, remains in the scar tissue. There are indications that histiocytes can also transform into fixed cells of connective tissue - fibroblasts. Cells of the reticuloendothelial apparatus (polyblasts and histiocytes) take particularly active part in the development of many specific granulomas. For example, they give rise to epithelioid and giant cells of tuberculous tubercle, lepromatous cells in lepromatous granuloma, typhoid and epithelioid cells in typhoid granuloma, Mikulicz cells in rhinoscleroma, pseudoxanthoma cells in granulation tissue in actinomycosis, etc. In the proliferations of granulation tissue in lymphogranulomatosis, cells of the reticuloendothelial apparatus also participate to a large extent in the form of various polyblastic and epithelioid cells and characteristic Sternberg cells. 17. Significance of reticuloendothelial cells in transplantation and in blastomatous growth. The question of the significance of the reticuloendothelial apparatus in the transplantation of normal tissues has been little studied. There are only fragmentary and contradictory indications that after blocking of the reticuloendothelial apparatus, homoplastic transplantation of tissues is much more successful. A larger amount of data exists regarding the significance of the reticuloendothelial apparatus in the transplantation of tumor tissues, although in this respect many contradictions are also noted. However, there is much data indicating that weakening the function of the reticuloendothelial apparatus by blocking leads to better engraftment of transplanted pieces of tumors. From this, some conclude that in the development of tumors, a decrease in the function of the reticuloendothelial apparatus is also of great importance. The removal of the spleen also has a stimulating effect on the growth of experimental tumors. 18. Systemic hyperplasias and tumors of the reticuloendothelial apparatus.

Systemic hyperplasia of cells of the R.-e. a. in a number of cases depends on their chronic irritation and loading with various products of intermediate metabolism. This includes hyperplasia of the R.-e. a. in disorders of lipid metabolism, in Niemann-Pick disease, Gaucher's disease, general hemosiderosis, etc. All these forms can be united under the name of metabolic systemic hyperplasias of the R.-e. a. The second group consists of hyperplasias of the R.-e. a., arising in connection with increased hematopoiesis, when foci of myelo- and erythropoiesis develop extramedullarily in organs everywhere, in the origin of which, according to existing views, cells of the R.-e. a. actively participate. This form of hyperplasia of the R.-e. a. can be called hemocytoblastic. The third group consists of hyperplasias on the basis of chronic irritation of the R.-e. a. by infectious agents, for example, in chronic sepsis, malaria, etc. This probably also includes lymphogranulomatosis as a particularly sharply expressed form of systemic hyperplasia of the R.-e. a., on the basis, as some think, of weakened tuberculous infection. From all the listed types of hyperplasia of the R.-e. a., which can be designated as symptomatic hyperplasias, it is necessary to distinguish idiopathic hyperplasias, developing without visible connection with any of the indicated functional irritants of the R.-e. a. This group includes: 1) leukemic and aleukemic reticulo-endothelioses (see) and 2) reticulo-endotheliomas of a tumor nature. Some authors object to the isolation of reticulo-endothelioses into a special group, pointing out that in them there is probably chronic septic irritation of the R.-e. a. Furthermore, it is very difficult to draw the line between these forms and lymphogranulomatosis. Hyperplasias of the R.-e. a. of a tumor nature are rare, although in recent times quite a few of them have been described. Usually, in this case, there is a tumor proliferation of reticular cells in some one area of the R.-e. a. with greater or lesser involvement of other parts in the process. These phenomena are most common in the lymphatic system, for example, in lymph nodes and the pharyngeal lymphatic ring. The interpretation of many cases attributed to this group, however, still remains controversial.