Healing of gastric ulcer. Studies on cell turnover in normal and H.pylori-infected rats

Abstract

A number of factors, such as the gastric contents, growth factors, trefoil peptides, hormones, nerve and H.pylori infection, may accelerate or delay gastric ulcer healing by influencing cell proliferation and cell death. We studied cell proliferation and apoptosis in gastric epithelium in normal rats and in rats with H.pylori infection. Special interest was devoted to rats in which an ulcer was induced in the gastric corpus. In normal rats, the labeling index of gastric epithelium was 2-5% in the corpus, 7% in the antrum and 25% in the duodenum. The turnover time of parietal cells was calculated to be 164 days. The frequency of apoptosis averaged 2 cells per mm mucosal length in both the corpus and the antrum. In the ulcer-operated rats, the labeling indices in the ulcer margin and in the duodenal crypts of Lieberkühn were significantly increased over the control. Immunoreactivities for epidermal growth factor (EGF) and EGF receptor were much stronger in the ulcer margin than those in normal mucosa. The gastric acid secretion stimulated by pentagastrin was reduced by 35% in ulcer-operated rats. Many of these changes observed after ulcer induction appear to be favorable for ulcer healing. Gastrin has a trophic effect on the oxyntic mucosa. Five days of hypergastrinemia, obtained by infusion of gastrin-17 or by administration of omeprazole or ranitidine, increased the labeling index by 30% in the ulcer margin. These results can explain the rapid gastric ulcer healing observed during acid inhibition. The turnover time of parietal cells was not significantly changed by the hypergastrinemia. A rat model of H.pylori infection was established by inoculating a mouse-adapted strain. In the rat model, H.pylori colonized the antral mucosa up to 12 months. The infection was accompanied by the progressively elevated serum levels of H.pylori-specific IgG2a, and by a mild to moderate mucosal inflammation. In the H.pylori-inoculated and -infected rats, ulcer healing was delayed, and the number of apoptotic cells in the corpus, antrum and ulcer margin was significantly higher than normal, while the labeling index of the gastric epithelium was not significantly altered. The markedly increased cell death in gastric epithelium may contribute to the delayed healing of gastric ulcer. The results revealed pathological and pathophysiological changes in the stomach of rats during gastric ulcer healing and during a long period of H.pylori infection. A multitude of factors influence ulcer healing by modulating cell proliferation and cell death. An important factor is H.pylori.