The long-term objective of the proposed research is to determine the roles played by polymorphonuclear leukocytes (PMN), chemotactic factors (e.g., complement [C5]-derived peptides), and endothelial cells (EC) in provoking the microvascular """"""""injury"""""""" that accompanies immunologically-mediated, acute inflammation in patients with rheumatic diseases. Attempts will be made to develop in vitro models in which we can compare adherence of PMN to blood vessel walls under """"""""normal"""""""" conditions and under conditions that might be found at sites of inflammation. Since PMN ordinarily do not adhere tightly to endothelial surfaces in vivo, experiments will be performed to determine factors that influence """"""""basal"""""""" adherence of human PMN to cultured human EC. Specific attention will be directed at chemotactic factor-induced adhesive interactions between PMN and EC. Results of our preliminary studies suggest that chemotactic factors not only increase the number of PMN that adhere to EC, but also increase the strength of adherence by increasing expression on the surface of PMN of a glycoprotein complex recognized by monoclonal antibody 60.3. Studies are planned to elucidate further the mechanism(s) by which chemotactic factors alter the adhesiveness of PMN. The hypothesis will be tested that lectin-like glycoprotein complex (recognized by 60.3) mediates attachment of PMN to EC, and that this complex is translocated from tertiary granules to the cell surface upon exposure of PMN to chemotactic factors. Finally, studies are planned to examine whether PMN interact differently with microvascular EC than with EC from large blood vessels. Since we have been able to maintain in culture EC derived from human umbilical veins and from the microvessels of human skin, it should be possible to test the hypothesis that microvascular EC possess unique properties which render them more susceptible than EC from large blood vessels to PMN-induced """"""""injury"""""""". These studies should provide significant new information concerning the roles played by PMN, EC and C5-derived peptides in the pathogenesis of acute, immunologically-mediated inflammation.
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