Benjamin W. Zweifach

Elastic Environment of the Capillary Bed

To determine the degree to which the capillary blood vessels in vivo are supported by the elasticity of the surrounding tissue, a study was made of the elastic properties of the mesentery of the rabbit. A torsion test was made on a circular membrane of the avascular region of the mesentery, by applying a graded static torque and measuring the resulting deformation. The mesentery was found to have a modulus of rigidity in the same category as that of larger arteries and veins. It has a nonlinear stress-strain relationship with a tendency to harden at larger strains. In torsion experiments, the shear modulus G can be reduced to the following form G = μ+c2|τ| Where c2 is a constant and |τ| is the absolute value of the shear stress. The constant μ depends on the initial tension in the membrane. For the mesentery specimens, μ ranges from 215 to 1900 gm/cm2, whereas the nondimensional constant c2 has an average value of 8.23 with a standard deviation of 2.1. The hypothesis is advanced that the medium in which the capillaries of the mesentery are embedded is a gel and the capillary in effect is a tunnel in this gel. Such a hypothesis could explain the apparent rigidity of the blood capillaries.

Selective Distribution of Blood Through the Terminal Vascular Bed of Mesenteric Structures and Skeletal Muscle1

in considerable detail, both in the living state and after fixation and staining, by numerous investigators. No particular emphasis was placed on the arrangement of the various vascular elements as discrete organic units around which the functional behavior of the bed was organized. In much of the earlier work, the peripheral vascular bed was depicted as an indiscriminately arranged network of capillaries which unite with one another to form venous channels (1). These findings were based chiefly on areas such as the interdigital web of the frog and the cutaneous and mesenteric structures in various mammals. Our own detailed

ADHESION AND EMIGRATION OF LEUKOCYTES PRODUCED BY CATIONIC PROTEINS OF LYSOSOMES.

A cationic protein fraction isolated from rabbit polymorphonuclear leukocyte lysosomes causes adhesion and emigration of leukocytes and petechial hemorrhage in the microcirculation of the rat and rabbit mesentery.

EFFECTS OF A SYNTHETIC ANALOGUE OF VASOPRESSIN ON VASCULAR SMOOTH MUSCLE.

Summary PLV-2, a synthetic analogue of vasopressin, applied topically to the micro-vessels in the rat mesoappendix produces a graded dose response reduction in true capillary blood flow. The various vessel types contract from the venular to the arteriolar loops; the opposite of their normal profile of reactivity. This polypeptide, when injected i.v. in a single dose potentiates constrictor responses to topically applied catecholamines. In contrast to these microcirculatory effects, PLV-2 inhibits norepinephrine-induced contractions in the isolated rabbit aortic strip.

THE CONTRIBUTION OF THE RETICULOENDOTHELIAL SYSTEM TO THE DEVELOPMENT OF TOLERANCE TO EXPERIMENTAL SHOCK

Before entering into a discussion of the mechanisms involved in different forms of tolerance to stress and their possible relation to the reticuloendothelial system (RES), it would be useful to catalogue the evidence linking disturbances in RES function to the development of shock. In a recent survey of the phagocytic behavior following protracted hemorrhagic shock in the rat’ it was shown that RES function became progressively impaired as the shock deepened. Subsequent studies in the rabbit showed a comparable effect coincident with the development of the irreversible stage of hemorrhagic shock. TABLE 1 shows that the phagocytic index K , measured by following the clearance of carbon from the blood stream, remains depressed for at least 24 to 48 hours after exposure to severe hemorrhagic shock. Conversely, it has been shown that interference with the RES, by overloading the phagocytic elements with large amounts of colloid, renders the animal highly sensitive to all forms of stress, including hemorrhagic and traumatic shock,% infusions of vasoactive amines, bacterial endotoxins,a exotoxins of bacterial origin, histamine, and whole-body X irradiation! The predisposing action of RES blockade is temporary in nature, lasting from 4 to 12 hours in most cases. The fact that a similar impairment of the capacity to withstand shock and endotoxemia develops in germ-free rats that have received blocking doses of colloidal iron would seem to rule out bacterial toxemia as the decisive factor affected by blockade of the RES.6 The precise mechanism involved must await clarification of the many changes in the blood constituents and in the vessels themselves, which have been shown to be activated by the injection of large amounts of colloidal suspensions and their uptake by the RES. Morphologic evidence also has been provided to show that the Kupffer’s cells of the liver and the phagocytes of the spleen undergo degenerative and inflammatory changes following various forms of shock and blockade.6 Inflammatory changes involving the phagocytes of the liver and spleen are most prominent in animals pretreated with colloidal thorium dioxide (Thorotrast) alone or subjected to shock after blockade with Thorotrast. As may be seen in FIGURE 1, clusters of neutrophils surround the damaged Kupffer’s cells in the liver as early as 8 to 10 hours after hemorrhagic shock (B.P. at 40 mm. Hg for 3 hours). There is thus a clear-cut history of disturbed reticuloendothelial function

Effect of hemorrhagic shock on the phagocytic function of Kupffer cells.

This report concerns the phagocytic behavior of the Kupffer cells in the rat during hemorrhagic studies by quantitative technics. The rate of clearance (measured by colloidal carbon) was suppressed by 50 per cent after 3 hours. Efficiency of clearance (measured by uptake of radioisotope labeled albumin and chromium phosphate) was likewise markedly below normal. This factor was not due to reduced blood flow through the liver, as evidenced by measurements made 1 hour after blood replacement. Histologic evidence suggests two possibilities: a localized impairment of Kupffer cell activity in the area about the central veins of the lobule, or an abnormal circulation through preferential pathways restricted to the periphery of the liver lobule.

The extravascular nature of Arthus reactions elicited by ferritin. A combined light and electron microscopic analysis of immune states in rabbit ear chambers and mesenteries.

SummaryRabbits were immunized with ferritin and were challenged with the antigen (1) by placing the ferritin on top of rabbit ear chamber tissue and (2) by placing it on top of immune mesentery. In immune animals, a brisk and mounting reaction was characterized by white blood cell sticking and emigration, thrombosis, stasis, vessel shutdown and necrosis. Electron micrographs of tissue taken from sites of injury revealed aggregates of electrondense material with a double density. The material appeared in the extravascular tissue, often perivascularly, inside and outside of white blood cells, the cells being virtually exclusively polymorphonuclear leucocytes. The clumps, presumably antigen-antibody complexes, were never found intraluminally. Ferritin was not found phagocytized by endothelial cytoplasm.The evidence permits the hypothesis that such reactions have their genesis in the extravascular deposition of immune complexes, not in the vessel wall as many observers have held.It is possible, however, that this may be a property of electron-dense high molecular antigens, such as ferritin, and not necessarily a general characteristic of reactions associated with hypersensitivity states of the Arthus type or of other types.It is the purpose of this communication to present the evidence that in the genesis of the Arthus reaction, the site for the reactants is in the extravascular tissue, not in the vessel wall. Subsequently, blood vessel injury occurs and, with it, the exudative phase of the reaction. This does not diminish the importance of the polymorphonuclear leucocyte in the reaction but, in perspective, it identifies white cell sticking and emigration, and endothelial injury, as relatively late events in the phenomenon. The evidence suggests that the early events of the Arthus reaction may involve white blood cells that have emigrated across capillary beds and are present in extravascular tissue before the stimulus provided by immune reactants. Such an hypothesis offers a unifying concept for the phenomenon and, if valid, explains many of the apparently disparate experimental facts surrounding the Arthus reaction.

SUBCELLULAR DISTRIBUTION OF SEROTONIN IN RABBIT PLATELETS.

Summary In rabbit platelets, serotonin has been qualitatively localized in the granule fraction in a bound form. The platelet membranes do not appear to contain bound serotonin. The existence of free (soluble) serotonin is likely, although at least part of the dissolved serotonin may have resulted from mechanical disruption of platelet granules.

Reactions of peripheral blood vessels in experimental hemorrhage.

The problem confronting the investigator in experimental shock is a complex one, involving as it does a multiplicity of changes which occur simultaneously in the circulatory system as a whole. Since the circulatory collapse during shock is essentially peripheral in origin, a systematic inquiry into the hemodynamics of the peripheral vascular apparatus seemed to offer a direct approach to some of the more fundamental aspects of the syndrome. By focusing attention on the peripheral vascular system as a discrete organic unit with its own special physiology, it was possible to demonstrate the relationship of specific defects in this system to the broad, overall features of the syndrome. The relative inaccessibility of the extreme peripheral portion of the vascular tree has made it the object of considerable speculation and has resulted in its being used as a convenient source of otherwise not-to-beexplained variations in the general circulation. The work of such pioneers as Krogh, Dale, Lewis, and Clark has demonstrated that the terminal ramifications of the arterial vascular tree are not merely a series of inert tubes which serve to bridge the gap between arteries and veins but represent discrete organic units whose delicately balanced activity controls the distribution of blood to the tissues. On this basis, the minutiae of the peripheral vascular apparatus, the terminal arterioles, precapillaries, capillaries, and venules are collectively referred to as the capillary bed, a system of vessels which possesses a considerable degree of independence from the circulation at large and is capable of responding selectively to tissue influences of both local and general origin. The complexity of the peripheral vascular apparatus makes it difficult to detect changes in its component structures without direct visualization of the vessels concerned. On the whole, the chief objection to previous observational studies on the peripheral circulation has been the failure to ascertain the extent to which traumatic disturbances, incidental to preparing the tissue for observation, interfere with the normal reactivity of the vessels. I t appeared essential, therefore, first, to make an intensive study of the mechanisms which integrate the distribution of blood through the capillary bed under normal conditions, and then to ascertain whether alterations in these mechanisms occur during secondary shock. Several groups of investigators1* have assigned the vascular lesion in shock to a generalized increase in capillary permeability, a hypothesis for which no supportive evidence has been forthcoming. In view of the precisely

Biologic Properties of Vascular Endothelium

The present report deals with aspects of the behavior of endothelium as viewed in the living microcirculation which are not adequately rejected in the static preparations used for electron microscopy. In general, one can assign three primary attributes to the capillary wall: (1) its function in the exchange of materials between the blood stream and the parenchymal cells; (2) its activities related to local defense mechanisms; and (3) its capacity to give rise to other cellular constituents found in or near the