PHYSIOLOGICAL, IMMUNOHISTOCHEMICAL AND MOLECULAR ASPECTS OF GASTRIC ADAPTATION TO STRESS, ASPIRIN AND TO H-PYLORI-DERIVED GASTROTOXINS

Gastric mucosa is continuously exposed to various aggressive factors s uch as stress, ulcerogenic drugs including aspirin-like agents, gastro toxic bacteria, particularly Helicobacter pylori (Hp) and many other e xogenous and endogenous irritants. The maintenance of mucosal barrier depends upon the activation of pre-epithelial (mucus-alkaline secretio n), epithelial (surface active phospholipids, mucosal cell restitution and proliferation) and post-epithelial (mucosal microcirculation) lin es of mucosal defence. The mucosa exposed to aggressive factors develo ps acute lesions, which usually heal completely within few days, but f ollowing repeated exposures to hostile environment it adapts to surviv e the challenge of noxious agents. This adaptation may be of short ter m (adaptive cytoprotection) and follows the exposure to ''mild'' irrit ants that activate local mucosal biosynthesis of protective prostaglan dins (PG) and nitric oxide (NO) and stimulate sensory nerves and mucos al cell migration and proliferation through enhanced expression of gro wth factors such as EGF, TGF alpha and trefoil peptides. The fact that exogenous PG, NO-donor agents, growth factors and capsaicin, stimulat ing sensory nerves, protect the mucosa against strong necrotizing agen ts (direct cytoprotection), supports the notion that endogenous PG, NO , growth factors and sensory nerves are involved in the complex proces s of adaptive cytoprotection. With repeated insults of ulcerogens such as stress, aspirin, Hp-derived gastrotoxins, especially ammonia, a lo ng-term adaptation develops which is mediated mainly by overexpression of EGF and TGF alpha and their common receptor (EGFR) with subsequent increase of mucosal cell proliferation and enhanced healing of mucosa l lesions. The failure of mucosal adaptation seems to play a pivotal r ole in the pathogenesis of gastric lesions and peptic ulcerations.