The complement proteins, which are predominately located within the plasma, are activated intravascularly during the early stages of myocardial ischemia and reperfusion, following protamine injection, during cardiopulmonary bypass surgery and hemodialysis. Inhibition of complement activation or depletion of complement proteins before or after myocardial ischemia and reperfusion has beneficial effects in reducing tissue injury. In preliminary data, the authors have shown that administration of a monoclonal antibody against the anaphylatoxin, C5a, in a porcine model of myocardial ischemia and reperfusion has beneficial effects in reducing tissue injury and maintaining left ventricular transmyocardial blood flow. The mechanisms of C5a-induced myocardial injury are poorly understood and are the focus of this proposal. In vitro and in vivo experiments are planned to investigate the effects of C5a on platelet and granulocyte (PMN) interactions. In vivo experiments will investigate the role of platelets and P-selectin in a model of C5a- induced myocardial ischemia. The hypothesis is that the in vitro generation of TxA2 by PMN requires the synergistic and direct interaction of PMN and platelets. The specific roles of the membrane adherence proteins CD18 and CD62 (P-selectin), platelet-activating factor and cathespin G will be investigated in mvitro using specific monoclonal antibodies and antagonists to examine the synergistic interaction of C5a-stimulated PMN and platelet suspensions in producing TxA2. The role of platelets and the membrane adherence protein, P-selectin in C5a- induced myocardial ischemia will be investigated in vivo. Selective depletion of platelets or inhibition of P-selectin function in vivo in acutely anesthetized pigs will attenuate C5a-induced myocardial ischemia and TxA2 production. The hypothesis is that C5a-induced myocardial ischemia results from the synthesis of TxA2 through the synergistic interaction of PMN and platelets involving P-selectin. An understanding of mechanisms underlying C5a's effects on coronary blood flow and the production of vasoactive metabolites may provide clinicians with a rationale for treating adverse clinical conditions associated with anaphylatoxin production.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL052886-03
Application #
2460075
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1995-08-01
Project End
1999-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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