Patients at risk for developing multiple organ failure following traumatic injury experience intestinal stasis (ileus) early in their course and ultimately succumb to colonization by bacteria indigenous to the gastrointestinal tract. The major goal of this project is to develop an understanding of how post-injury ileus and its associated bacterial overgrowth contributes to a breakdown in the remarkably impervious mucosal barrier to enteral bacteria and toxins. Sprague-Dawley rats will be used to elucidate the potential role of bacterial toxins (formyl- methionyl leucyl phenylalanine-FMLP), and endotoxin lipopolysaccharide-LPS) in the mucosal dysfunction that accompanies analogues of traumatic stress (ischemia/reperfusion-IR, morphine analgesia-MS, and enteral deprivation-ED with total parental nutrition- TPN). Loops of proximal and distal small bowel will be perfused with varying concentrations of FMLP and LPS under acute and chronic conditions to assess the role of IR, MS, and ED/TPN on sensitizing the mucosa to toxin exposure. Mucosal permeability, inflammatory mediator release, brush border peptidase activity, and FMLP bioavailability will be assessed. Mucosal cells will be examined for FMLP and C5a receptors. Signal transduction and paracellular shunt pathways will be studied with a focus on the classic neurogenic inflammatory pathway that involves serotonin-substance P release from enteric nerve endings-mast cell mediators. Substance P depleted (capsaicin), mastocytotic (trichinella spirilis) and mastopenic (irradiated) rats will be used for this purpose. The modulatory roles of prostanoids, reactive oxygen intermediates, and nitric oxide will be studied using agonist, antagonist methodology. Therapeutic strategies to include bacterial decontamination, enteral nutrition, carboxypeptidase perfusion, and pro-kinetic motor stimulation will be evaluated in the bacterial toxin model that most closely reflects the clinical course of patients with multiple organ failure.
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