The mechanism, whereby histamine and serotonin increase the permeability of blood vessels, was studied in the rat by means of the electron microscope. The drugs were injected subcutaneously into the scrotum, whence they diffused into the underlying (striated) cremaster muscle. An intravenous injection of colloidal HgS was also given, in order to facilitate the identification of leaks by means of visible tracer particles. After intervals varying from 1 minute to 57 days the animals were killed; the cremaster was fixed, embedded in methacrylate, and examined with the electron microscope.One to 12 minutes after the injection, the blood vessels of the smallest caliber (3 to 5 micra as measured on electron micrographs) appeared intact. Numerous endothelial openings were present in blood vessels with a diameter of 7 to 8 micra or more. These gaps were 0.1 to 0.8 micra in width; portions of intercellular junctions were often present in one or both of the margins. The underlying basement membrane was morphologically intact. An accumulation of tracer particles and chylomicra against the basement membrane indicated that the latter behaved as a filter, allowing fluid to escape but retaining and concentrating suspended particulate matter of the size used.Uptake of tracer particles by endothelial vesicles was minimal. Phagocytosis by endothelial cells became more prominent at 3 hours, but as a secondary occurrence; the pericytes were actively phagocytic at all stages. At the 3-hour stage no leaks were found.The changes induced by histamine and serotonin were indistinguishable, except that the latter was more potent on a mole-to-mole basis. In control animals only small accumulations of tracer particles were found in the wall of a number of blood vessels.With regard to the pathogenesis of the endothelial leaks, the electron microscopic findings suggested that the endothelial cells become partially disconnected along the intercellular junctions. Supporting evidence was provided at the level of the light microscope, by demonstrating-in the same preparation--the leaks with appropriate tracer particles ~, and the intercellular junctions by the silver nitrate method. The lipid nature of the chylomicron deposits observed in electron micrographs was also confirmed at the level of the light microscope, using cremasters fixed in formalin and stained in toto with sudan red.Almost a century has elapsed since Cohnheim's "New Studies on Inflammation" (1): the monograph in which Virchow's former assistant ana See accompanying paper.nounced, for the first time, that acute inflammation must involve an increased permeability of the blood vessels. This concept was slow in gaining acceptance (2) perhaps because it did not fit 571 on
Previous work has shown that endogenous chemical mediators, of which histamine is the prototype, increase the permeability of blood vessels by causing gaps to appear between endothelial cells . In the present paper, morphologic and statistical evidence is presented, to suggest that endothelial cells contract under the influence of mediators, and that this contraction causes the formation of intercellular gaps . Histamine, serotonin, and bradykinin were injected subcutaneously into the scrotum of the rat, and the vessels of the underlying cremaster muscle were examined by electron microscopy . To eliminate the vascular collapse induced by routine fixation, in one series of animals (including controls) the root of the cremaster was constricted for 2-4 min prior to sacrifice, and the tissues were fixed under conditions of mild venous congestion . Electron micrographs were taken of 599 nuclei from the endothelium of small blood vessels representing the various experimental situations . Nuclear deformations were classified into four types of increasing tightness (notches, foldsl closing folds, and pinches. In the latter the apposed surfaces of the nuclear membrane are in contact) . It was found that : (1) venous congestion tends to straighten the nuclei in al groups ; (2) mediators cause a highly significant increase in the number of pinches (P < 0 .001), also if the vessels are distended by venous congestion ; (3) fixation without venous congestion causes vascular collapse . The degree of endothelial recoil, as measured by nuclear pinches, is very different from that caused by mediators (P < 0 .001) . (4) Pinched nuclei are more frequent in leaking vessels, and in cells adjacent to gaps (P < 0 .001) ; (5) mediators also induce, in the endothelium, cytoplasmic changes suggestive of contraction, and similar to those of contracted smooth muscle ; (6) there is no evidence of pericyte contraction under the conditions tested . Occasional pericytes appeared to receive fine nerve endings. Various hypotheses to explain nuclear pinching are discussed ; the only satisfactory explanation is that which requires endothelial contraction .
Contracting granulation tissues contain fibroblasts that develop characteristics typical of smooth muscle: (a) They contain an extensive cytoplasmic fibrillar system. (b) They show immunofluorescent labeling of their cytoplasm with human anti-smooth muscle serum. (c) The nuclei show complicated folds and indentations, indicative of cellular contraction. (d) There are cell-to-cell and cell-to-stroma attachments. (e) It is possible to extract similar quantities of actomyosin (having the same adenosine triphosphatase activity) from granulation tissue and from pregnant rat uterus. (f) Strips of granulation tissue, when tested pharmacologically in vitro, behave similarly to smooth muscle. All these data support the view that, under certain conditions, fibroblasts can differentiate into a cell type structurally and functionally similar to smooth muscle and that this cell, the "myo-fibroblast," plays an important role in connective tissue contraction.
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