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 such as stress, ulcerogenic drugs including aspirin-like agents, gastrotoxic bacteria, particularly Helicobacter pylori (Hp) and many other exogenous and endogenous irritants. The maintenance of mucosal barrier depends upon the activation of pre-epithelial (mucus-alkaline secretion), epithelial (surface active phospholipids, mucosal cell restitution and proliferation) and post-epithelial (mucosal microcirculation) lines of mucosal defence. The mucosa exposed to aggressive factors develops acute lesions, which usually heal completely within few days, but following repeated exposures to hostile environment it adapts to survive the challenge of noxious agents. This adaptation may be of short term (adaptive cytoprotection) and follows the exposure to "mild" irritants that activate local mucosal biosynthesis of protective prostaglandins (PG) and nitric oxide (NO) and stimulate sensory nerves and mucosal cell migration and proliferation through enhanced expression of growth factors such as EGF, TGF alpha and trefoil peptides. The fact that exogenous PG, NO-donor agents, growth factors and capsaicin, stimulating sensory nerves, protect the mucosa against strong necrotizing agents (direct cytoprotection), supports the notion that endogenous PG, NO, growth factors and sensory nerves are involved in the complex process of adaptive cytoprotection. With repeated insults of ulcerogens such as stress aspirin, Hp-derived gastrotoxins, especially ammonia, a long-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 mucosal lesions. The failure of mucosal adaptation seems to play a pivotal role in the pathogenesis of gastric lesions and peptic ulcerations.
Konturek
P C
PC
Department of Medicine I, University of Erlangen-Nuremberg, Germany.
D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D000818:Animals; D001241:Aspirin / Q000009:adverse effects*; D001427:Bacterial Toxins / Q000633:toxicity*; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D013315:Stress, Psychological / Q000473:pathology / Q000503:physiopathology*
D018712:Analgesics, Non-Narcotic; D001427:Bacterial Toxins; D001241:Aspirin