Search

Various stressors induce apoptosis in gastric mucosal cells, which may cause gastric mucosal lesions in vivo. We recently reproduced gastric stressor-induced apoptosis in vitro, using primary cultures of guinea pig gastric mucosal cells. Geranylgeranylacetone is an antiulcer drug with heat-shock protein-inducing properties. The purpose of this study is to examine the effect of geranylgeranylacetone on gastric stressor-induced apoptosis in vitro. Ethanol, hydrogen peroxide, and hydrochloric acid all induced, in a dose-dependent manner, apoptotic DNA fragmentation. Pretreatment of cells with geranylgeranylacetone inhibited the apoptotic DNA fragmentation caused by each of these gastric stressors. Pretreatment of cells with a low concentration of ethanol, a procedure that is also known to induce heat-shock proteins, made cells resistant to the apoptotic DNA fragmentation. These results suggest that heat-shock proteins could be at least partly involved in the inhibitory effect of geranylgeranylacetone against apoptosis of gastric mucosal cells caused by these gastric stressors.

Guinea pig gastric pit cells in primary culture undergo serum-dependent cell maturation, which mimics their maturation in vivo. In this study we compared the sensitivities of these cells, as a function of early- and late-stage cell maturation, to various gastric stressors. Gastric pit cells in the early stage of maturation (two days of culture) were more resistant to apoptotic cell death induced by exposure to hydrogen peroxide than those cells in late-stage maturation (three days of culture). This maturation-associated difference was not observed for the sensitivities of cells to necrotic cell death induced by hydrogen peroxide, nor for necrotic and apoptotic cell death induced by other gastric stressors (ethanol and hydrochloric acid). The activities of catalase and glutathione peroxidase were specifically decreased in cells at the late stage of maturation compared to those at the early stage. The relative gastric pit cell phenotype sensitivity to hydrogen peroxide at the late stage of maturation may be due to a decrease in the activities of catalase and glutathione peroxidase, which are antioxidants for hydrogen peroxide.

Prostaglandins have cytoprotective effects on gastric mucosa via the influence of various mechanisms. The purpose of this study is to examine the effects of prostaglandins on maturation-dependent spontaneous apoptosis in gastric mucosal cells in vitro, which mimics the apoptosis of gastric mucosal cells related with a rapid cell turnover rate in vivo. Both prostaglandin E1 and E2 inhibited spontaneous apoptosis in a dose-dependent manner and increased the viability of gastric mucosal cells in culture. A number of antiulcer drugs presently in clinical use were shown to increase the concentrations of prostaglandins in cells. All of the drugs tested clearly inhibited the spontaneous apoptosis in a dose-dependent manner. Based on these results, we propose that the cytoprotective effects of prostaglandins on gastric mucosa in vivo can be partially explained by an increase in the number of gastric mucosal cells present as a result of the inhibition of maturation-dependent spontaneous apoptosis.

We previously reported that various gastric irritants induced both apoptosis and necrosis in cultured gastric mucosal cells. In a continuation of this work, the present study has examined the effects of prostaglandin E2 (PGE2), a cytoprotective factor for gastric mucosa in vivo, on gastric irritant-induced apoptosis and necrosis in vitro. PGE2 inhibited ethanol-induced apoptosis and increased cell viability in a dose-dependent manner in primary cultures of guinea pig gastric mucosal cells. PGE2 also inhibited hydrogen peroxide-induced apoptosis. In contrast, PGE2 showed no cytoprotective effects against ethanol-induced necrosis. Based on these results, we consider that the cytoprotective effects of PGE2 on gastric mucosa in vivo can be partially explained by its inhibitory effect on gastric irritant-induced apoptosis.