Mucosal Irritation, Adaptive Cytoprotection, and Adaptation to Topical Ammonia in the Rat Stomach

Abstract

Background: The urease-ammonia (NH₄OH) system has been proposed to play a major role in the pathogenesis of the Helicobacter pylori-associated gastritis, but the mechanism of the mucosal damage has not been fully explained. This study was designed to examine possible adaptive cytoprotection and the adaptation of rat gastric mucosa to the irritant action of NH₄OH and urease. Methods and Results: Single application of NH₄OH alone in various concentrations (15-500 mM) caused concentration-dependent mucosal damage starting with 30 mM and reaching a maximum at 250 mM NH₄OH, similar to that obtained with 100% ethanol; it was accompanied by a decrease in gastric blood flow (GBF) to ~ 30% of the normal value. When the mucosa was first exposed to the low, non-damaging concentration (15 mM) of NH₄OH and then insulted with 100% ethanol, the extent of ethanol damage was greatly attenuated as compared with that caused by ethanol alone. This adaptive cytoprotection was accompanied by the rise in GBF and reversed, in part, by the pretreatment with indomethacin, an inhibitor of prostaglandin (PG)-cyclooxygenase; with L-NAME, a blocker of NO-synthase; or with capsaicin deactivating the sensory nerves. Damaging concentrations of NH₄OH (125 mM) caused widespread mucosal damage after the first application, but with repeated insults with 125 mM NH₄OH a gradual reduction in the mucosal lesions, accompanied by enhanced mucosal cell proliferation and overexpression of epidermal growth factor (EGF) (using immunocytochemistry) and mRNA of EGF (using trans-reverse polymerase chain reaction), were observed. Conclusions: NH₄OH alone damages gastric mucosa only at the concentration exceeding that found in H. pylori-infected stomachs, whereas at lower concentrations it acts as ‘mild’ irritant to induce adaptive cytoprotection. This adaptive cytoprotection appears to be mediated, in part, by endogenous PG, sensory nerves, and an arginine-NO-dependent pathway, and repeated applications of NH₄OH induce gastric adaptation, probably mediated by enhanced expression of EGF and its receptors and by an increased cell proliferation.

Key Words:

• Ammonia
• cytoprotection
• gastric adaptation
• mucosal growth