description): This study is focused on the neutrophil mediated tissue injury during inflammation of the reperfused myocardium. The application is revised according to previous review as a R29. The general premise is that the severity of reperfusion injury appears to be a greater risk factor in hearts of diabetics than in non-diabetics. Thus, the central hypothesis is that enhanced neutrophil recruitment and activation is responsible for greater vulnerability of diabetic myocardium to ischemic/ reperfusion induced tissue necrosis. The applicant proposes to investigate the molecular mechanisms involved in the inflammatory response that is associated with reperfusion injury in a db/db strain of diabetic mice and in streptozotocin treated mice. The experimental plan will utilize an in vivo model of coronary artery ligation and reperfusion. Monoclonal antibodies will be used for in vivo quantification of endothelial cell adhesion molecules (ECAM). The extent of neutrophil accumulation, contractile function, and cell necrosis will also be examined to assess the vulnerability of the diabetic heart to ischemia/reperfusion damage. The applicant also intends to evaluate anti-inflammatory therapies on ECAM expression, leukocyte recruitment, and cell damage. Several strains of transgenic mice, as knockout models of cytokine or cell adhesion molecule deficiencies, are also to be tested for the extent of reperfusion injury following streptozotocin treatment.
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