This proposal represents a continuing 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 derived from our past studies of the complement pro-inflammatory serum protein system suggests that, in model reperfusion injury of several organs, the complement response causes more of an injury than the original ischemic insult itself. Accordingly, inhibition of complement activation by a variety of means or in a variety of genetically modified mice has produced a diminution in the degree of final injury. Therefore, we hypothesize that major injury is critically exacerbated by the autologous inflammatory response. We wish (1) to understand the mechanism by which injured tissue activates the inflammatory response, (2) to understand the specific sequence of events leading from an ischemic insult to inflammatory activation, (3) to modify the antibody-binding component of the immune system activation caused by reperfusion injury, (4) to fully characterize human reperfusion injury and attempt to ameliorate it with the knowledge gained from this grant to date, and (5) to 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 (Project I) will provide the financial support for the knock-out mice used by 3 of the projects, the data support for the clinical project, and the administrative support for the overall grant and its outreach programs. Project II will use techniques of molecular biology to identify potential neoantigens on injured tissue. Project III will investigate and modify a range of murine B1 cell natural antibody clones to fully define the role of natural antibody in reperfusion injury. Project IV will investigate the role of mast cell degranulation in the genesis of reperfusion injury and resulting complement activation. Project V will characterize human mesenteric reperfusion injury utilizing newly available techniques. By this funding mechanism, we wish to efficiently, and by multiple techniques, arrive at specific therapy for mesenteric reperfusion injury, the related injury of other organ systems, and an avenue of prevention for organ failure following massive traumatic injury and its accompanying shock.
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