Gastric mucosal ulceration continues to be a major health care problem, often necessitating surgical intervention due to the ineffective capabilities of managing this entity medically and its high recurrence rate after initial healing. The underlying difficulty in managing this disease relates to our current lack of knowledge regarding the precise mechanisms responsible for the pathogenesis of gastric epithelial injury and ulcer formation. A considerable body of knowledge indicates that prostaglandins (PGs) have the amazing capability of markedly reducing the magnitude of gastric damage histologically when induced under a wide variety of experimental circumstances. In studies with these fatty acids, it has become increasingly clear that injury can occur within a matter of a few minutes after exposing the gastric epithelium to a given damaging agent and that Pgs can protect against such injury within an equal time frame. While the mechanisms underlying the ability by which Pgs mediate their protective properties has remained elusive, it is quite well established that it is rapid, efficient, and consistent morphologically. Of the multiple mechanisms that have been proposed to explain this protective property, the vast majority have had to be eliminated since they would take too long to become operational. In view of the time frame in which gastric injury occurs and PG protection is mediated, a likely mechanism for this circumstance is the generation of oxygen derived free radicals by damaging agents and the prevention of such oxidant formation by Pgs. Considerable data has been obtained during our most recent funding period supporting this hypothesis. Using the rat as our experimental animal, we plan to continue our studies to determine specifically what role oxidant formation plays in gastric injury and protection.
Five specific aims will be addressed. These include: (1) determination of whether known oxygen radical scavengers or inhibitors can prevent gastric mucosal injury induced by established damaging agents; (2) determination of whether endogenous glutathione plays a role in gastric mucosal injury and defense; (3) determination of whether pathologic derangements induced by damaging agents can be altered by oxygen radical scavengers, sulfhydryls, and Pgs; (4) identification of the mechanisms by which oxygen radicals are generated in gastric mucosa in response to damaging agents; and (5) determination of whether enzymes modulating oxygen radical formation are influenced by damaging agents and Pgs. By addressing these considerations, an enormous amount of important information is likely to be obtained which will have direct bearing on enhancing our understanding of the pathogenesis of gastric injury and ulceration with the expectation that such knowledge can be used to effect better treatment strategies for these disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Surgery and Bioengineering Study Section (SB)
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University of Texas Health Science Center Houston
Schools of Medicine
United States
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Leung, Anna M; Redlak, Maria J; Miller, Thomas A (2009) Aspirin-induced mucosal cell death in human gastric cells: role of a caspase-independent mechanism. Dig Dis Sci 54:28-35
Redlak, Maria J; Power, Jacinda J; Miller, Thomas A (2008) Prevention of deoxycholate-induced gastric apoptosis by aspirin: roles of NF-kappaB and PKC signaling. J Surg Res 145:66-73