Sepsis is the leading cause of death in intensive care units in the United States, with up to 210,000 people dying from the disease annually. Gut epithelial apoptosis is elevated in both animal models and human autopsy studies of sepsis. We have previously demonstrated that gut-specific overexpression of the anti- apoptotic protein Bcl-2 is associated with improved survival following murine models of sepsis. These studies have been performed in 6-16 week old mice, which correspond to previously healthy 10-17 year old patients. This population almost never gets septic, and afflicted patients have only a small chance of dying if they do develop the disease. In contrast, the vast majority of clinical sepsis occurs in aged patients or those with severe pre-existing co-morbidities. It is known that aged septic animals respond markedly different to therapy than young septic animals, suggesting that young, previously healthy animals might not be appropriate surrogates for septic patients in intensive care units. In this application, the effect of preventing sepsis- induced gut epithelial apoptosis in either aged animals or those with cancer will be determined. Mechanisms underlying the survival advantage conferred by gut overexpression of Bcl-2 will be determined and will be compared and contrasted between young, previously healthy animals, aged animals, and animals with neoplasia. Since sepsis is a systemic disease, mechanistic studies will examine how preventing gut epithelial apoptosis influences the immune system. These experiments will be performed because apoptotic cells are immunosuppressive and preventing cell death should have secondary effects on immune cell distribution and function. In addition, there is well- established """"""""crosstalk"""""""" between the gut and the immune system suggesting changes in one cell type will alter the other. Alternative anti-apoptotic therapies to prevent sepsis- induced cell death will also be evaluated in pneumonia, to determine if this approach decreases mortality in a disease which starts with a local pulmonary insult but kills patients in large part due to secondary systemic effects.
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