The goal of this Trauma Research Center is to identify therapeutic interventions that can modulate gastrointestinal (GI) inflammation and resulting gut dysfunction in critically injured patients to improve outcome. Traumatic shock initiates a series of events that, in severe cases, can lead to systemic inflammatory response syndrome (SIRS) or multiple organ failure (MOF). This proposal will test the hypothesis that one of the early events in the development of GI inflammation after trauma is an attenuation in the surface hydrophobic barrier that serves to protect the underlying GI epithelium, and that the mechanism for this involves bile salts and one or more phospholipase enzymes. The hydrophobic barrier of the stomach and intestines is composed primarily of the phospholipid, phosphatidylcholine, that lines the mucus layer and prevents the back diffusion of acid, bacterial toxins and other noxious elements in the GI lumen. Disruption of this hydrophobic lipid layer by bile salts or phospholipases in the GI lumen may allow potentially damaging factors to have access to the underlying epithelium and contribute to pathogenic processes. Replenishing the lipid layer with exogenous phospholipid may be a means to intervene therapeutically.
The aims of this proposal are: 1) to investigate a role for disruption of the gastric surface hydrophobic barrier in the etiology of lipopolysaccharide (LPS)-induced gastric inflammation and injury, and is so doing to define the pathophysiological and molecular events (e.g., bile acid reflux, induction of phospholipase A2 and cyclooxygenase-2) associated with this change in biophysical state; 2) to examine the efficacy of phosphatidylcholine and other potential therapeutic regimens on the LPS-induced reduction of gastric surface hydrophobicity and the development of mucosal inflammation; and 3) to determine the utility of analyzing the gastric juice collected from trauma patients for the appearance of potential GI damaging factors, phospholipids and their metabolic products, and indices of GI inflammation as a determinant of clinical outcome. These studies will contribute important new information concerning the pathogenic mechanisms associated with LPS and the prediction and treatment of GI inflammation and injury after trauma.
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