Mechanisms of Intestinal Apoptosis in Sepsis and Shock

Washington University, Saint Louis MO

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Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Sepsis kills at least 120,000 people annually in the United States. Gram negative sepsis induces excess gut epithelial apoptosis, and intestinal overexpression of the anti-apoptotic protein Bcl-2 improves survival in murine models of 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, and that the gut's own endogenous bacteria also ncrease intestinal apoptosis and decrease host survival in sepsis. The first aim of this investigation is to identify pathways through which pathogenic bacteria induce intestinal cell death. Utilizing a variety of infections, transgenic and knockout animals with alterations in the mitochondrial or receptor-mediated pathways of cell death will be assayed to determine how sepsis-induced gut epithelial apoptosis is mediated. The next aim is to determine if inhibition of gut cell death via each pathway decreases host mortality. Using genetically altered mice, studies will be performed to see if specifically inhibiting intestinal cell death through either the mitochondrial or receptor-mediated pathways improves survival in sepsis. Mechanisms that may underlie this survival advantage will also be examined, including altered gut permeability and interactions between the gut epithelium and the host's adaptive immune system. The third aim is to determine if the gut's endogenous bacteria induce apoptosis and decrease survival in intraabdominal sepsis. Gut apoptosis, pathways of cell death and survival will be compared between germ-free mice that lack an endogenous microflora and conventional mice with intraabdominal infection. Germ-free mice will then be colonized with single members of the gut's own flora to determine their impact on cell death and host survival. Transgenic animals with gut Bcl-2 overexpression will then be rederived as germ-free to determine if their survival iadvantage in sepsis depends on the gut's endogenous flora. [unreadable] [unreadable]