Effects of acid inhibitors on progression of gastric atrophy and development of gastric cancer in Helicobacter pylori-infected gastric mucosa.

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Aims : H.pylori (Hp) produces high concentrations of ammonia by high urease activity. The present study was conducted to clarify the mechanisms by which ammonia disrupts gastric mucosal barrier function and induces apoptosis of gastric epithelial cells.Methods : 1. In vitro study : (1) Effects of ammonia (NH4Cl) on apoptosis of GSM06 cells, epithelial cell line derived from mice gastric mucosae were examined in vitro. (2) Effects of NH4Cl on electrophysiology and morphology of intact sheets of gastric fundic mucosae were examined in vitro. 2. In vivo study : Effects of prolonged use of acid inhibitors (H2-blocer, PPI) on gastric inflammation and gastric atrophy were examined in C57/BL6 mice infected with Hp.Results : 1. In vitro study (1) NH4Cl induced apoptosis of GSM06 cells, an effects augmented at high ambient pH.(2) NH4Cl decreased in potential difference and resistance, and induced cytoplasmic vacuolation in gastric glands especially at high luminal pH.2. In vivo study : Prolonged use of acid inhibitors such as proton pump inhibitors or H2-blockers exacerbated gastritis and apoptosis, accelerated atrophy in body, but not in antrum, in Hp-positive, but not in Hpnegative mice.Conclusions : Prolonged acid inhibition exacerbates body gastritis, enhances apoptosis of gastric gland, and accelerates body atrophy, in Hp-infected gastric body mucosa effects mediated by conversion of ammonia from NH4^+ to NH3 during acid inhibition.