Title

The role of arachidonic acid metabolism in intestinal pathogenesis

Date of Completion

January 2010

Keywords

Biology, Cell

Degree

Ph.D.

Abstract

Arachidonic acid (AA) metabolism is a critical process mediated by a number of enzymes that control physiological and pathological functions. The first study demonstrates that administration of COX-inhibitors to mice with a genetic deletion in cPLA2 causes acute lethality within two weeks, with no effect on wild-type littermates. Morbidity was a result of severe GI damage with associated bacteremia and sepsis. Further analysis revealed genes involved in ATP generation to be differentially expressed when comparing genotypes after drug administration. cPLA2-/- mice had morphological damage of enterocytic mitochondria with subsequent impairment of ATP generation. This study demonstrates a protective role for AA generation against drug-induced GI toxicity related to mitochondria] damage and impaired function. The second study examines the protective roles of PGs against ulcerative colitis (UC). Administration of dextran sodium sulfate (DSS) to mice with a genetic deletion in cPLA2 induced greater clinical and pathological disease as compared to wild-type littermates. A subsequent study demonstrated that DSS exposure to mice with a genetic deletion in mPGES-1 also suffered more extensive acute disease than wild-type littermates. mPGES-1-/- mice were also shown to be impaired in their ability to recover from DSS-induced injury related to expansion of colonic ulcerations. This study demonstrates a protective role for PGE2 against susceptibility to acute UC disease as well as recovery. The third study investigates the impact of the inflammatory response on intestinal tumorigenesis. Exposure of DSS to APCmin/+ mice with a genetic deletion of mPGES-1 decreases intestinal tumor number, with no effect in APCmin/+ mice. No changes in epithelial markers within tumors were observed in any group, but examination of tumor-associated myeloid derived suppressor cells showed impaired ARG-1 expression. This study demonstrates that DSS administration to a mouse model that has an altered inflammatory response results in decreased intestinal tumor development. Taken together, these three studies demonstrate the protective roles of components of the AA metabolism cascade in the GI tract. ^