Molecules, released from ischemic cardiac cells, provides signals which activate the complement cascade and increase the expression of cell surface molecules which mediate leukocyte adherence to vascular endothelium. As a result, leukocytes are sequestered in ischemic tissues where they exacerbate the injury caused by hypoxemia. A unique canine model which permits continuous access to both the circulation and cardiac lymph will be used to: A) Identify molecules in heart muscle which activate the complement cascade. B) Enumerate and identify intracellular, complement-reactive molecules which are released into the extracellular fluid by ischemic cardiac cells. C) Identify and characterize molecules which mediate adherence of neutrophils to endothelium. D) Quantitatively evaluate strategies designed to suppress complement activation and leukocyte chemotaxis and adherence in ischemic myocardium. Thus, treatment with serine protease inhibitors, antisera to Cir and Cis and other complement components, as well as monoclonal and polyclonal antisera specific for leukocyte cell surface receptors, such as the CD 18 receptors for C3bi, which facilitates adherence of leukocytes to endothelial surfaces, will be tested to evaluate whether these can reduce localization of complement and/or retard the accumulation of radio-labeled autologous leukocytes in ischemic myocardium. Sensitive serological assays will also be developed to characterize C1q binding molecules frequently detected in sera of patients with myocardial infarction but only rarely in sera of controls who have chest pain without infarction. We postulate that these complement-reactive molecules may be intracellular components of myocardial cells. Thus one outcome of the proposed studies may be the development of new serologic methods to diagnose myocardial necrosis. These investigations reflect a collaborative effort of 3 laboratories, each of which have different but complementary skills, which are working together to develop novel methods to identify and control the fundamental mechanisms responsible for myocardial injury attributable to complement activation and the localization and degranulation of leukocytes in ischemic heart tissue.
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