Arachiodonic acid is converted to prostaglandins by cyclooxygenase (COX), an enzyme with two isoforms: COX-1, which is constitutive, and COX-2 which is inducible by cytokins and phorbol esters. Inhibitors of prostaglandin synthesis (like NSAID) are associated with gastrointestinal epithelial toxicity in the general population and with clinical exacerbation in patients with inflammatory bowel disease. However, the biochemical bases of this association have not been defined. Using the irradiate mouse model of wound healing, it has been determined by the applicant that manipulation of prostaglandin levels significantly impact on the ability of the intestinal epithelium to recover from injury. Preliminary studies with dextran sodium sulfate (DSS) - induced colitis in mice, a model relevant to inflammatory bowel disease, also suggest an important role of prostaglandins in regulation of intestinal epithelial regeneration after injury. Immunohistochemical studies reveal that COX-1 is expressed in lamina propria mononuclear cells and in areas of the crypt epithelium corresponding to the proliferative zone. DSS treatment decreases the number of proliferative cells per crypt. Moreover, the decrease in number of proliferative cells due to DSS is prevented in mice concomitant treated with 16, 16 dimethyl prostaglandin E2. The central EZ, promote wound healing in inflammatory bowel disease that inhibition of prostaglandins synthesis impairs wound healing. A secondary hypothesis is that DSS reduces epithelial cell prostaglandin production, which in turn inhibits epithelial cell proliferation and healing, and that this impaired would healing is the mechanism of DSS-induced gastrointestinal injury.
Specific aims are 1) characterize prostanoid synthesis and epithelial cell regeneration in the acute and recovery phase of DSS colitis in mice; 2) determine the effect of exogenous prostaglandins and COS inhibitors on regeneration of the epithelium in the recovery phase of DSS-induced colitis; 3) define the prostanoid receptors and intracellular mechanisms involved in prostaglandis-mediated recovery of the epithelium; 4) define the mechanisms of DSS-induced changes inepithelial prostaglandins production and COX expression using epithelial cell lines and COX-1 knockout mice.
Showing the most recent 10 out of 53 publications
