Microcirculation : the official journal of the Microcirculatory Society, Inc
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The objectives of this study were to develop a model for studying endothelin-1-mediated eNOS regulation in cultured sinusoidal endothelial cells and determine the effect of endothelin-1 and endotoxin (LPS) on eNOS localization. ⋯ These studies demonstrate an LPS-mediated uncoupling of endothelin receptor activation and eNOS translocation. This functional uncoupling may, in part, account for the hyperconstrictive effects of endothelin-1 during inflammatory conditions.
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Obese patients with sepsis have higher morbidity and mortality than lean counterparts, but the mechanisms involved are unknown. The authors examined the inflammatory and thrombogenic responses of the cerebral microvasculature to sepsis induced by cecal ligation and perforation in obese and lean wild-type mice. ⋯ These findings suggest that the increased morbidity to sepsis in obesity may result from exaggerated microvascular inflammatory and thrombogenic responses that include the activation of endothelial cells with subsequent expression of adhesion molecules, such as P-selectin.
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Shock is accompanied by a severe inflammatory cascade in the microcirculation, the origin of which has been hypothesized in the past to be associated with specific mediators such as endotoxin, oxygen free radicals, nitric oxide, cytokines, and lipid products. But no intervention with clinical effectiveness has been derived from these ideas to date. The authors propose here a new hypothesis suggesting that degradative enzymes, synthesized in the pancreas as part of normal digestion, may play a central role in shock and multiorgan failure. ⋯ Digestive enzymes thereby gain access to the wall of the intestine and initiate self-digestion of submucosal extracellular matrix proteins and interstitial cells. The process leads to generation and release of a host of strong inflammatory mediators. The authors hypothesize that inhibition of pancreatic enzymes in the lumen of tile intestine can serve to attenuate formation of these inflammatory mediators in ischemic tissues following hemorrhagic shock, and consequently prevent cell and tissue injury as well as multiorgan failure.
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This review evaluates (1) the regulation of water and solute transport across the endothelial barrier in terms of pore theory and the glycocalyx-junction-break model of capillary permeability; and (2) the mechanisms regulating permeability based on experiments using cultured endothelial cells and intact microvessels. ⋯ The current form of the glycocalyx-junction-break model of capillary permeability describes the selectivity of the capillary wall (pore size) in terms of the space between the fibers of a quasi-periodic matrix on the endothelial cell surface, and the area for exchange (pore number) in terms of the length and frequency of breaks in the tight junction strands. An independent test of this model in a range of mammalian microvascular beds is new experimental evidence that the colloid osmotic pressure of plasma proteins is developed across the glycocalyx, not across the whole microvessel wall. We are beginning to understand that endothelial cells may change their phenotype in response to physical and chemical stresses. Such changes in phenotype may explain changes in the regulation of endothelial barrier function in intact microvessels that have previously been exposed to injury and differences in the regulation of contractile mechanisms between endothelial cells in vivo and in vitro.
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To characterize the hepatic leukocyte endothelial cell interactions occurring in early sepsis and to determine whether this is influenced by fluid treatment. ⋯ Hepatic leukocyte recruitment occurs early in sepsis. Pentastarch in a balanced solution but not in normal saline significantly reduces hepatic leukocyte recruitment, suggesting solution composition, as well as osmolarity impact the innate immune response.