Previous studies have indicated that the gastric mucosa normally is protected from the damaging effects of luminal acid by preventing diffusion of acid from the lumen into the mucosa and neutralizing or disposing of H+ ions entering the tissue. Impairment of these protective properties, rather than hypersecretion of acid is generally held to be the cause of acute mucosal erosions elicited by topical agents of injury or systemic sepsis or stress. Recent work in isolated gastric epithelial systems, however, has suggested: 1) that transport and permeability processes located in the basolateral (i.e. serosal-side) cell membrane regulate intracellular ion composition and pH; 2) that processes leading to basolateral uptake of HCO3- or extrusion of H+ may depend substantially on cotransport or exchange mechanisms with Na+, K+ or C1-; and 3) that topical agents of injury such as aspirin or bile salts may not only reduce the resistance of the epithelium to back-diffusion of acid, but they may directly impair these cellular mechanisms of H+ neutralization or disposal. To further define these protective mechanisms at the cellular level, the proposed studies are designed: 1) to identify basolateral mechanisms which regulate intracellular levels of Na+, K+ and C1-; 2) to examine the basolateral co-transport mechanisms by which the cell uses these ions to take up HCO3- or extrude H+ in order to preserve cell pH; 3) to evaluate the effects of topical agents of injury on the cell's ability to handle experimental acid loads, independent of their effects on permeability to luminal acid. These three sets of specific aims will be pursued using intracellular microelectrode techniques in an in vitro model of surface epithelium from the gastric antrum of the amphibian, Necturus maculosus. The first set will be addressed by defining the contributions of the different permeability and transport properties which regulate intracellular levels of Na+, K+ and C1-. These studies will also examine the influence of changes in luminal acidity and nutrient composition on the processes which regulate intracellular levels of these ions. The second set of studies will be directed at identifying specific processes such as Na+/H+ or C1-/HCO3- exchange in the cell's ability to buffer an acid load and evaluating the dependence of these processes on intracellular ion composition. Further studies will evaluate the influence of cellular regulatory agents such as prostaglandin or cAMP on the cell's ability to maintain ion composition and pH during experimental acid loading. The final set of studies will evaluate the effects of two well known ulcerogens, aspirin and bile salt, on processes which regulate cell ion composition and whether alterations in these processes would impair the cell's ability to neutralize or dispose of influxing H+ ions. The proposed studies should provide, at the cellular level, a more detailed understanding of the protective functions of the gastric surface epithelium and of the disturbances of cell transport and permeability properties which occur in different ulcerogenic conditions.
