This proposal represents a highly integrated examination of the mechanisms by which injured tissue elicits a response from the host and one of the harmful effects of this response. Data which from our past study of the complement pro-inflammatory serum protein system suggests that, in many circumstances, the complement responses causes more of an injury than the original insult itself. Accordingly, inhibition of complement has led to a diminution in the degree of final injury. Therefore, we hypothesize that major injury is critically exacerbated by the autologous inflammatory response. We wish to (1) understand the mechanism by which injured tissue activates the inflammatory response, (2) understand the sequence of events leading from the injury's local injured tissue to the inflammatory attack directed against it, (4) to compare the inflammatory response to injury to the response generated by other insults, and (5) synthesize these data to produce an effective therapeutic strategy to reduce the degree of tissue damage which results from a specific injury occurrence. The Trauma Center Core will provide the forum with which to focus the group of four investigators in their examination of the interrelationship of complement with antibodies and tissue metabolism. by utilizing shared animal models, assays, facilities, and intellects. Project one will relate changes in cellular energetics and membrane metabolism to indicators of inflammatory attack utilizing NMR technology in models of ischemia and reperfusion injury. Project two will assess the interplay of serum complement and lymphocyte natural antibody repertoire in the production of post-injury inflammation. The third project will investigate both novel methods of complement inhibition and the interaction of local injury with remote injury. The fourth project will assess changes in injured tissue membrane proteins with a goal of antibody based therapy. By this funding mechanism, we wish to efficiently and by multiple techniques assess the veracity of our primary hypothesis and to postulate therapies more specific than global inhibition of serum complement.
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