Gastrointestinal (GI) mucosal injury from insults such as ethanol, bile, and aspirin continues to be a major health care problem, often necessitating hospitalization, and occasionally surgery. The underlying difficulty in managing this disorder relates to the current lack of understanding regarding the precise mechanism(s) responsible for its pathogenesis. A considerable body of knowledge indicates that prostaglandins (PGs) have the amazing capability to markedly reduce the magnitude of GI 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 stomach and/or intestine to a given damaging agent and that PGs can protect against such injury within an equal time frame. The observation that both gastric and intestinal epithelium damaged by various insults under in vitro conditions can have this damage prevented or markedly attenuated when treated with PGs indicates that neurovascular elements as well as humoral factors are not necessary for PG's protective action to occur. The applicants have recently observed that ethanol damage is associated with alterations in intracellular calcium at the same time it disrupts microtubule stability. They have further observed that PG pretreatment can prevent these perturbations concomitant with its protective action. Based on these observations they believe that maintenance of cellular microtubule integrity through stabilization of intracellular calcium may be a fundamental mechanism by which PGs mediate the cellular protective action, and provides a unifying hypothesis to explain the underpinnings of GI injury and protection. To validate this hypothesis, the specific aims during this new grant period will be 1) to identify the role of intracellular calcium accumulation in gastrointestinal injury and protection, 2) to identify the signal transduction mechanism(s) responsible for PG-induced cytoprotection in gastric and intestinal cells exposed to damaging agents, and 3) to determine the role of microtubule disassembly in gastrointestinal injury and its prevention by PGs as a target of protection.
| 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 |
