CELLULAR MECHANISMS OF SEPSIS AND ORGAN FAILURE

Washington University, Saint Louis MO

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Abstract

Sepsis induces widespread apoptotic cell death in immunologic cells (e.g., thymocytes, splenocytes, and lymphocytes) and parenchymal cells in selected organs. Therefore, apoptosis may be an important cause of immunologic suppression in sepsis by causing extensive lymphocyte depletion. Alternatively, apoptosis may be beneficial by down- regulating the inflammatory response which accompanies sepsis. The degree to which parenchymal cell apoptosis contributes to multiple organ failure (MOF) remains unknown. The aims of this proposal are to determine the beneficial or detrimental effects of apoptosis on organ system function and survival in sepsis. In addition, the role oxidant injury and increases in intracellular calcium as potential triggers of apoptosis in sepsis will be determined. Finally, the molecular pathway of apoptosis in sepsis will be dissected using transgenic mice with selected defects in the presumed pathway. Studies will be conducted in mice using the cecal ligation and perforation (CLP) model of sepsis. Oxygen radical production and intracellular calcium concentration will be measured using in vivo fluorescent laser scanning confocal microscopy. Evidence of apoptosis also will be sought in biopsy samples of human liver, muscle, and vascular endothelial cells and white blood cells (neutrophils and lymphocytes) from critically ill septic patients and critically ill non- septic patients. Apoptosis will be confirmed by both morphologic methods (laser scanning confocal microscopy and electron microscopy) and by molecular biology methods (DNA agarose gel electrophoresis).