Sepsis kills at least 120,000 people annually in the United States. The gut has long been proposed to be the """"""""motor"""""""" of the systemic inflammatory response, and increased intestinal apoptosis is a potential mechanism underlying the gut's role in critical illness. We have previously shown that gut epithelial apoptosis is increased in both animal models and human autopsy studies of sepsis. Further, intestinal overexpression of the anti-apoptotic protein Bcl-2 improves survival in murine models of gram negative pneumonia and appendicitis. The central hypothesis of this proposal is that gut apoptosis plays a critical role in mediating decreased host survival through both mitochondrial and receptor-mediated pathways in either gram positive or gram negative sepsis. We will first identify pathways through which pathogenic bacteria induce intestinal cell death utilizing a variety of infections to verify results are not model specific. The functional significance of this will be shown by determining if altering gut cell death via intestine-specific modulation of cell death pathways or downstream apoptotic signaling improves host survival. Next, we have demonstrated that sepsis-induced gut death is dependent on crosstalk with lymphocytes. Lymphocyte subsets responsible for this interaction will be determined, as will cellular, tissue, and systemic mechanisms underlying how lymphocytes alter gut epithelial apoptosis in sepsis. Finally, sepsis-induced gut apoptosis normally occurs in the presence of the intestine's endogenous bacteria. Since the gut's microflora influences host epithelial biology under basal conditions, we will determine its significance in sepsis by eliminating it. Using germ-free animals that lack endogenous bacteria and colonizing them with single members of the gut's own flora, we will determine how gut bacteria affect intestinal epithelial apoptosis if these mice are subsequently made septic. We will then rederive transgenic mice that overexpress gut Bcl-2 to be germ-free to determine the functional relationship between the intestine's endogenous flora and epithelial apoptosis in sepsis.
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