Cardiopulmonary bypass profoundly alters the interacting coagulation and immune systems, resulting in seemingly contradictory coagulopathic, prothrombotic, immunosuppressive and proinflammatory diatheses that are responsible for cardiopulmonary bypass related pulmonary and myocardial injury and bleeding early during bypass and hypercoagulability and immunologic disturbances later in cardiopulmonary bypass. As demonstrated previously under this grant, cardiopulmonary bypass results in a dynamic alteration in platelet-leukocyte-erythrocyte-endothelial adhesive and functional interactions, in part initiated by terminal membrane component generation. Using in-vivo studies and in-vitro whole blood model and a simulated extracorporeal circulation model, the PI has shown that antigenic and functional upregulation of specific beta2 integrins occurs on circulating phagocytes in cardiopulmonary bypass, platelet alpha-granule release and P-selectin expression occurs with formation of circulating platelet -leukocyte conjugates during cardiopulmonary bypass at anti-complement C5 monoclonal antibody blocks both platelet and neutrophil activation during simulated extracorporeal circulation. Further work suggests that damaged and reticulated red blood cells promote activated platelet microparticle formation, that platelet activation may be a result of C5b-9 while adhesion molecule upregulation occurs a consequence of C5a activity. Furthermore, neutrophil granule release and adhesion upregulation are separable events and reticulated platelets represent a platelet subset which shows differential functional activity and may by preferentially lost during cardiopulmonary bypass.
The aims of this application are to 1) define which complement components and other mediators initiate which parameters of platelet white blood cell endothelial activation 2) to define the molecular basis of erythrocyte-platelet-white blood cells interactions which generate cellular and soluble mediators of coagulation and inflammation in cardiopulmonary bypass and to define alterations in endothelial cells inducted by simulated extracorporeal circulation using an addition to the current model. The long term goals of these studies is to develop therapeutic strategies to alleviate complications of extracorporeal circulation and to understand the basic biology of platelet-white blood cell-erthyrocyte-endothelial interactions.
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