Our working concept, over the last several years, has been that the vascular endothelial lining plays an active role in regulating the temporal and spatial patterns of acute inflammatory responses. In particular, previous work in this Project has identified two endothelial- dependent mechanisms especially relevant to neutrophil recruitment -- endothelial-leukocyte adhesion molecule 1 (ELAM-1,-E-SELECTIN) and endothelial-derived interleukin-8 (IL-8). ELAM-1 is an inducible endothelial cell surface glycoprotein that interacts selectively with leukocytes (including neutrophils) that bear a complex carbohydrate ligand (sialyl-Lewis), and supports their adhesion and transmigration in In vitro models. lL-8 is a cytokine, secreted by endothelium and other cells, that functions as a neutrophil activator and chemoattractant, but can also act as an inhibitor of adhesion and transmigration, both in vitro and in vivo. The genes encoding these inflammatory components are normally silent in the uninflamed vascular endothelial cell, but can be strongly induced by certain inflammatory stimuli such as bacterial endotoxin (LPS), interleukin-1 (IL-1) and tumor necrosis factor (TNF), and their products have been detected in inflamed tissues and body fluids in humans and experimental animals. It is our working hypothesis that the regulated expression of these endothelial-dependent mechanisms is important for the orderly development and resolution of acute inflammatory reactions, and that their """"""""dysregulated expression"""""""" may lead to tissue and organ damage. The overall objective of this continuing project, in the next period, will be to develop experimental models (in vitro, in vivo) that make use of molecular biological and genetic approaches to selectively overexpress or underexpress ELAM-1 and IL-8 in vascular endothelial cells, and utilize these models to gain new insights into the role of these endothelial- dependent mechanisms in acute inflammatory disease processes.
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