Role of epidermal growth factor, prostaglandin, and sulfhydryls in stress-induced gastric lesions.

Epidermal growth factor promotes the growth of and protects gastric mucosa against various ulcerogens, including stress, but little is known about its role in the pathogenesis of stress ulcerations. In this study, Wistar rats with intact and resected salivary glands were exposed to water-immersion and restraint stress. During 2-14 hours of water-immersion restraint stress, the formation of gastric ulcerations increased progressively and the duration of stress was accompanied by a decrease in DNA synthesis in the gastric mucosa. Following sialoadenectomy, a significant increase in the number of stress ulcerations and further reduction in DNA synthesis were observed. Exogenous epidermal growth factor and dimethyl prostaglandin E2 significantly reduced the ulcerations in the stressed rats with intact salivary glands, but this reduction was significantly less pronounced after sialoadenectomy. Water-immersion restraint stress also resulted in about 50% reduction in mucosal prostaglandin E2 generation, and the pretreatment with indomethacin, which suppressed prostaglandin E2 by about 90%, almost doubled the number of stress ulcerations and abolished the gastro-protective effect of exogenous epidermal growth factor (but not dimethyl prostaglandin E2) against the stress lesions. An inhibition of ornithine decarboxylase activity by difluoromethyl ornithine also augmented stress-induced ulcerogenesis and abolished the protective action of epidermal growth factor while the administration of spermine almost completely prevented stress ulcerations in rats both without and with pretreatment with difluoromethylornithine. Water-immersion restraint stress also significantly reduced mucosal content of glutathione. Cysteamine increased tissue glutathione and reduced stress ulcerations but N-ethylmaleimide, an sulfhydryl blocker, decreased mucosal content of glutathione without affecting the stress ulcerations. This study indicates that the stress ulcers are accompanied by the reduction in mucosal synthesis of DNA, prostaglandin, and glutathione and that the presence of salivary glands attenuates the stress ulcerogenesis probably by releasing epidermal growth factor which acts, in part, by enhancing ornithine decarboxylase activity, mucosal growth, and prostaglandin and glutathione formation.