Hans Selye and the development of the stress concept. Special reference to gastroduodenal ulcerogenesis.

Hans Selye has a historic role in the development of the stress concept. Before his short article in Nature in 1936, the neuroendocrine response to nonspecific injury was thought to be restricted to the release of catecholamines, as recognized by Cannon. Selye was the first to appreciate the crucial role of the adrenal cortex/hypophysis axis in the stress response. He also insisted on the nonspecificity of this neuroendocrine response, and he named the stress-causing agent "stressors". His last major contribution was the distinction between negative, that is, distress, and positive, that is, eustress reactions. The "triad of stress" (adrenal hypertrophy, gastrointestinal ulcers, thymolymphatic atrophy) was also first described by Selye, who was fascinated by the fact that in stressed rodents only gastric and not duodenal ulcers would develop. It was not until the recognition of duodenal ulcerogenic properties of propionitrile and cysteamine as well as the subsequent quantitative structure-activity studies predicting the duodenal ulcerogenic action of complex molecules that pathogenetic investigations allowed a molecular and mechanistic approach for studying the etiology and pathogenesis of duodenal ulceration. Recent studies on the role of sulfhydryls, TRH, ET, and growth factors provide new insights into central and peripheral pre-ulcer pathways. We were surprised to learn that an organ-specific ET-1 release may play a role both in ulcer induction and healing, which seems to start with the expression of immediate early genes such as egr-1 and stimulation of the local synthesis of growth factors such as bFGF and PDGF. Thus, a historic review originating with Hans Selye and extending through the next 60 years allows a cellular and molecular approach to the better understanding of stress-related disorders such as gastroduodenal ulceration.