The long-term goals of this project are to elucidate mechanisms that mediate non-steroidal anti-inflammatory drug (NSAID) effects on cell migration, and use the knowledge gained to develop novel strategies for treatment and prevention of drug-induced ulcers. NSAIDs are used widely in humans and performance horses. Adverse side-effects include oral, gastric, duodenal, and colonic ulceration. The mechanisms underlying this gastro-intestinal toxicity are not completely clear. Laboratory investigations suggest that mucosal cyclooxygenase (COX) inhibition and loss of protective prostaglandins may be insufficient to explain NSAID enteropathies. Modulation of cellular polyamines represents one convergence point for multiple pathways involved in the regulation of intestinal epithelial cell migration. Experiments proposed here are designed to test the hypothesis that NSAIDs inhibit normal intestinal epithelial cell migration by depleting intracellular polyamines, inhibiting epithelial Kv channel expression, and depolarizing epithelial Era, thereby reducing the [Ca2+]i available to trigger cell migration via Ca2+-dependent signaling pathways. A series of NSAIDs with variable ulcerogenic potential and variable selectivity for COX isoenzymes will be studied.
The specific aims of the project are: 1) Correlate the effects of NSAIDs on intraceUular polyamine content and IEC migration. 2) Determine the effects of NSAIDs on the signal transduction pathways that modulate polyamine-dependent IEC migration. 3) Determine the effects of NSAIDs on barrier restitution after injury to native intestinal epithelium. The data obtained will be valuable to the physicians and veterinarians who prescribe NSAIDs for their patients, and need to understand the pathogenesis of NSAID toxicity. Most significantly, knowledge gained from these studies will advance the long-term goal of discovering novel strategies for treatment and prevention of NSAID-induced ulcers and strictures.
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