INTESTINAL EPITHELIAL WOUND HEALING: NSAIDS AND CALPAIN INHIBITION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goals of this project are to elucidate mechanisms that mediate non-steroidal anti-inflammtory drugs (NSAIDs) effects on cell migration during wound healing, and use the knowledge gained to develop novel strategies for treatment and prevention of gastrointestinal (GI) ulcers. Adverse GI effects of NSAIDs in humans and other species include oral, gastric, duodenal, and colonic ulceration. Despite extensive investigation, the mechanisms responsible for NSAID-associated GI damage are not completely understood. NSAIDs may promote ulcer formation, not only by inhibiting mucosal cyclooxygenase (COX) and decreasing cytoprotective prostaglandins (PG), but also by adversely influencing intestinal microflora, neutrophil recruitment, surface hydrophobicity and epithelial restitution. Recent evidence suggests that calpains (cysteine proteases) are vital to the several key pathways of fibroblastic and WBC migration. Our preliminary data indicate that ulcerogenic NSAIDs either down-regulate calpain gene expression or up-regulate the constituent inhibitor, calpastatin. From a global perspective this has led us to hypothesyze that the formation of NSAID-induced GI ulceration is due, in part, to inhibited epithelial and fibroblastic cell migration, facilitated neutrophil migration into the wound, leading to an uncoupled and uncoordinated wound healing response setting the stage for a chronic inflammatory state. The experiments proposed here are designed specifically to link NSAID inhibition of cell migration with NSAID effects on events vital to calpain function within differentiated intestinal epithelial cells (IECs). The specific aims of this project are to: 1) Demonstrate that calpains are critical to normal IEC migration. 2)Confirm that calpains are a target for NSAID-toxicity and disruption of intestinal epithelial wound healing. 3) Determine the effects of NSAIDs on the downstream substrates of the calpains, specifically cytoskeletal and intregin elements required during intestinal epithelial restitution. The results of this project will provide valuable data immediately useful not only to the health care providers who want to make rational decisions about prescribing NSAIDs, but also to the industrial scientists who strive to develop less toxic alternatives to the drugs currently available. Escalating concerns about serious cardiovascular complications linked to celecoxib and rofecoxib, the NSAIDs associated with lowest incidence of drug-induced gastropathy, draw attention to the urgent need for improved understanding of the mechanisms that underlie NSAID-induced ulcers.