The overall objective of the program project grant proposed in this application is to characterize the origin and pathophysiological role of inflammation in the course of early myocardial ischemia. Substantial experimental evidence supports the concept that localization of activated granulocyte contributes strongly to myocardial injury associated with ischemia and reperfusion. Evidence presented in the proposal gathered in our laboratories suggest that inflammatory events begin very early after the onset of myocardial ischemia. Our work suggest that molecules, released expression of cell surface adherence molecules which mediate leukocyte agreation and leukocyte adherence vascular endothelial cells and cardiac myocytes. The proposal addresses the following general objectives: A) Evaluate the time course and pathophysiological significance of the events involved in the development of inflammation in models of early myocardial ischemia as a function of extent and degree of ischemia. B) Identify and characterize tissue adherence molecules which mediate agreation, tissue adherence and transmigration of neutrophils in myocardial ischemia. C) Evaluate the role of reactive oxygen as an inflammatory stimulus itself as a catalyst in production of lipid derived leukotactic factors which may participate in initiation or modification of the inflammatory response. D) Identify, clone, and prepare antibody reagents to modify the reactivity of tissue adherence molecules in the endothelium an cardiac myocyte to which neutrophils adhere. E) Evaluate modifiers aimed to alter specific steps in the leukocyte inflammatory cascade. These modifying agents will be evaluated in vitro an in vivo for efficacy with respect to the specific step at which they are aimed and, subsequently, a potential therapeutic regimen may evolve.
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