Sepsis and noninfectious inflammation lead to organ dysfunction and death in greater than 230,000 people annually in the United States alone. Recent studies demonstrate that sepsis and noninfectious inflammation induce excess intestinal epithelial apoptosis in both animal models of critical illness and in human autopsy studies. The central hypothesis of this new laboratory is that increased gut epithelial apoptosis is detrimental in critical illness, and that decreasing levels of cell death will improve experimental survival. Since previous descriptive studies showing elevated intestinal epithelial apoptosis in sepsis and noninfectious inflammation cannot distinguish whether altered gut apoptosis has a functional significance in critical illness, the first aim of this investigation is to demonstrate that inhibiting gut epithelial apoptosis through mechanistically distinct strategies decreases mortality in diverse models of critical illness. Gut epithelial apoptosis will be selectively targeted using transgenic mice that overexpress Bcl-2 in their intestinal epithelium. Gut-directed caspase inhibitors will also be utilized. These apoptosis- inhibition strategies will be complemented with a novel apoptosis-acceleration strategy using the antilymphocyte antibody, anti-CD3 which causes a 40-fold induction of gut epithelial apoptosis. Mechanisms that may underlie the survival advantage conferred by a decrease in gut apoptosis will be investigated as well. Gut permeability studies will be performed using the ex vivo everted gut sac model on transgenic animals that overexpress intestinal Bcl-2 and their control littermates after induction of sepsis or noninfectious inflammation and. Interactions with the immune system will be assessed by the development of mice that simultaneously overexpress Bcl-2 in their intestinal epithelium but are deficient for T- and B- lymphocytes (Rag-1 mice). Throughout these studies, four models of critical illness will be utilized varying the site of injury (intraabdominal vs. lung) and type of infection (polymicrobial vs. monomicrobial).
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