The objective of this project is to examine the roles of complement and leukocytes in the pathogenesis of """"""""post-perfusion syndome"""""""" (PPS) after cardiopulmonary bypass (CPB) and to determine if inhibition of complement activation and depletion of leukocytes by mechanical filtration can prevent the syndrome. A role for complement in tbe pathogenesis of PPS has been suggested by studies demonstrating complement activation during CPB and by correlation of the severity of PPS with degree of complement activation; however, tbe hypothesis that complement is tbe cause of PPS has not been conclusively proven. Tbe recent availability of a unique strain of C3-deficient dogs and of a novel complement inhibitor makes examination of this hypothesis now possible. A canine experimental model of CPB has already been developed and has demonstrated pulmonary and hematologic manifestations of PPS; use of C3-deficient dogs in this model will provide opportunity to elucidate complement's role in PPS injury. Soluble human complement receptor type I (sCR1) is a potent inhibitor of complement activation produced by recombinant DNA techniques sCR1 reduces myocardial reperfusion injury in animal models. A porcine CPB model that demonstrates manifestations of PPS will be used to test the efficacy of sCR1 in prevention of organ injury and inflammation caused by CPB. That leukocytes also participate in PPS injury is supported by the observation of neutrophil sequestration in organs damaged by CPB. Preliminary work with a mechanical leukocyte filter in the CPB circuit has shown marked reduction in circulating leukocytes and less neutrophil sequestration in the lung. The proposed research will evaluate use of these filters in canine and porcine models, and will examine their effect on other viscera, as well as on the blood-borne mediators of inflammation. This proposal exploits a long history of collaboration between cardiac surgery, cardiology, immunology and pathology in this institution. It is hoped these models will not only lead to better understanding of complement and neutrophils in the inflammatory process of PPS, but also to clinically applicable means to ameliorate PPS. Mollification of PPS would significantly improve the safety of cardiac surgical procedures, mechanical circulatory assistance, and extracorporeal membrane oxygenation (ECMO).
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