Experiments described in this proposal are based on the hypothesis that major traumatic injury and related stressors may induce gut dysfunction that contributes to multisystem organ failure (MOF). This Trauma Research Center brings together a multidisciplinary team of basic and clinical scientists who have joined their respective areas of expertise and knowledge with the goal of determining, in relevant animal models, factors in gut dysfunction following traumatic stress. The major objectives to achieve this goal are: 1) To determine the pathological mechanisms that contribute to gut stasis following traumatic stress and develop strategies to restore normal gut propulsion; 2) To identify at the cellular level the perturbations within the gut mucosa that allow the transmigration of enteric bacteria and endotoxin following traumatic stress and develop ways to prevent this process; 3) to characterize the role of eicosanoids, oxygen-derived free radicals, and nitric oxide in regulating the normal and stressed splanchnic circulation and organ function, and 4) To determine if immunosuppression or anergy in the intestine, resulting from radiation-induced injury to the GI tract, can be prevented or alleviated through nutritional means. To achieve these objectives, rats and opossums will be exposed to major clinical elements of traumatic stress (hemorrhage with reinfusion, oral food deprivation, total parenteral nutrition, morphine analgesia, inflammation, infection, endotoxemia, and irradiation), with appropriate controls and safeguards for their welfare. Intestinal and biliary motility, bacterial translocation, splanchnic circulation and eicosanoid biosynthesis, and gut wall immunity will be studied with appropriate methodologies. The role of inflammatory mediators (cytokines, oxygen-derived free radicals) and nitric oxide will be examined at the cellular and molecular levels using intact animals and in vitro, tissue preparations. The results of these studies should provide a clear answer as to whether gut wall function is altered under these experimental conditions of traumatic stress. If such is the case, then early restoration of gut function may emerge as a strategy for the prevention of this highly lethal syndrome.
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