This proposal represents a highly integrated examination of the mechanisms by which injured tissue elicits a response from the host and of the harmful effects of this response. Data which from our past study of the complement response pro-inflammatory serum protein system suggests that, in many circumstances, the complement response 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 inflammatory reaction to remote, secondary organ damage, (3) to directly relate the metabolic changes of an injured tissue to the inflammatory attack directed against it, (4) to compare the inflammatory response to injury to the response generated by infectious 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 five investigators in their examination of the interrelationship of complement with cytokines, adhesion molecules, and tissue metabolism by utilizing shared animal models, assays, facilities, and intellects. Project one ill examine the effect of complement activation o n macrophages and the role of complement in a cytokine-driven model of multiple system organ failure. The second project 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 three will assess the interplay of complement and adhesive mediators, as well as defining the state of injured tissues' autoprotective membrane protein apparatus. The fourth project will assess changes in injured tissue membrane proteins and address the problem of specific therapy. A final, shared, aspect of the Trauma Center will be the testing of hypotheses in a series of human observational protocols. 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.
Showing the most recent 10 out of 34 publications
