The Cardiovascular System

Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear neutrophils (PMNs) at the site of inflammation causes endothelial dysfunction and tissue injury. The vascular endothelium plays an important role in passage of macromolecules and inflammatory cells from the blood to tissue. Under the inflammatory conditions, oxidative stress produced by PMNs leads to the opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier. The migrated inflammatory cells not only help in the clearance of pathogens and foreign particles but also lead to tissue injury. The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress-mediated signaling mechanisms that are involved in inflammation and tissue injury.

Reactive Oxygen Species in Inflammation and Tissue Injury

Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100–300 nm in diameter) An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined The microenvironment was modulated: (i) spatially, by growing tumors in subcutaneous or cranial locations and (ii) temporally, by inducing vascular regression in hormone-dependent tumors Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 12 μm This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm Albumin permeability was independent of pore cutoff size These results have three major implications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) delivery may be reduced during tumor regression induced by hormonal ablation, and (iii) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter

https://www.pnas.org/content/pnas/95/8/4607.full.pdf

Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment

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(1), 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.

/pdf/studies-on-inflammation-i-the-effect-of-histamine-and-2ar7sgielk.pdf

STUDIES ON INFLAMMATION: I. The Effect of Histamine and Serotonin on Vascular Permeability: An Electron Microscopic Study

Endothelial cells, which form the inner cellular lining of blood vessels and lymphatics, display remarkable heterogeneity in structure and function. This is the first of a 2-part review focused on phenotypic heterogeneity of blood vessel endothelium. This review provides an historical perspective of our understanding of endothelial heterogeneity, discusses the scope of phenotypic diversity across the vascular tree, and addresses proximate and evolutionary mechanisms of endothelial cell heterogeneity. The overall goal is to underscore the importance of phenotypic heterogeneity as a core property of the endothelium.

Phenotypic Heterogeneity of the Endothelium: I. Structure, Function, and Mechanisms

While it is an established fact that histamine and serotonin increase the permeability of blood vessels, the exact portion of the vascular tree which is so affected has not been conclusively demonstrated. The present study was undertaken to clarify this point. Our experiments were based on a method to which we refer as "vascular labeling," and which permits one to identify leaking vessels by means of visible accumulations of foreign particles within their walls. The mechanism of the labeling, elucidated by previous electron microscopic studies, is the following. Histamine and serotonin cause the endothelial cells of certain vessels to separate, and thus to create discrete intercellular gaps. Plasma escapes through these gaps, and filters through the basement membrane. If the plasma has been previously loaded (by intravenous injection) with colloidal particles of a black material such as carbon or mercuric sulfide, these particles—too large to pass through the basement membrane—will be retained and accumulate in visible amounts within the wall of the leaking vessel. This method is used to maximal advantage if the tissue is cleared and examined by transillumination in toto, so that leaking vessels can be accurately identified in their relationship to the vascular tree. As a test tissue we used the rat cremaster, a laminar striated muscle which can be easily excised with its vascular supply virtually intact. The rats were prepared with an intravenous injection of carbon or HgS, and a subcutaneous injection into the scrotum of histamine, serotonin, or NaCl (as a control). The injected drug diffused into the underlying cremaster and the vessels became labeled. One hour later, when the carbon had been cleared from the blood stream, the animal was killed. The cremaster was excised, stretched, fixed in formalin, cleared in glycerin, and examined by transillumination under a light microscope. The lesions induced by histamine and serotonin were identical. The leaking vessels, as indicated by the carbon deposits, always belonged to the venous side of the circulation. The heaviest deposits were found in venules 20 to 30 micra in diameter. The deposits decreased towards larger venules up to a maximum diameter of 75 to 80 micra, and towards the finer vessels until the caliber reached approximately 7 micra. Essentially spared by the deposits were the finest vessels, 4 to 7 micra in diameter, and constituting an extensive network oriented along the muscular fibers. By killing animals at varying intervals after the injections, it was found that the carbon particles were slowly removed from the vascular walls by the action of phagocytic cells. After 10 months there was still enough carbon locally to be recognized by the naked eye.

/pdf/studies-on-inflammation-ii-the-site-of-action-of-histamine-q1ji2tunsw.pdf

Gutta I. Schoefl

Papers

STUDIES ON INFLAMMATION : II. The Site of Action of Histamine and Serotonin along the Vascular Tree: A Topographic Study

Studies on inflammation. iii. growing capillaries: their structure and permeability.