Ulceration of the gastric mucosa continues to be a major health care problem, often necessitating surgical intervention due to the inability to effectively manage this entity medically and its high recurrence rate after initial healing. The difficulty in managing this disease relates to our current lack of knowledge regarding the mechanisms underlying the pathogenesis of gastric ulcer formation. Current evidence 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 conditions. In studies with these fatty acids, it has become 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. Whatever the mechanism by which PGs mediate their protective properties, it is clear that it is rapid, efficient, and consistent morphologically. The speed with which PGs mediate their protective effects has necessitated a rethinking of the processes responsible for this action. In the experiments outlined in this grant proposal, efforts will continue to be employed to determine the histologic correlates of gastric mucosal injury and protection in both in vivo and in vitro experimental models using the rat and dog stomach, and the conditions under which such protection is optimal. Efforts will also be undertaken to identify the mechanisms responsible for the protective action of PGs. Specifically, a role for the mucus-bicarbonate barrier and gastric blood flow in protection will be reassessed using time-sequence studies to determine whether changes in these parameters occur in the time frame in which protection is observed. Further, the possible role of glutathione and/or oxygen-derived free radicals in gastric injury and protection will be carefully assessed. Much has already been learned about the ulcerogenesis of the stomach by studying the protective action of PGs. By continuing to learn more about the extent to which PGs are protective under various experimental circumstances and the mechanisms by which this action is mediated, our knowledge concerning the processes of injury and protection in the gastric epithelium will most certainly be enhanced and in turn provide a more solid basis for prevention and treatment of mucosal damage and ulceration in the human stomach.
| 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 |
