Transforming growth factor alpha protection against drug-induced injury to the rat gastric mucosa in vivo.
This study was designed to determine whether transforming growth factor alpha (TGF alpha) protects rat gastric mucosa against ethanol- and aspirin-induced injury. Systemic administration of TGF alpha dose-dependently decreased 100% ethanol-induced gastric mucosal injury; a dose of 50 micrograms/kg delivered intraperitoneally 15 min before ethanol decreased macroscopic mucosal injury by > 90%. At the microscopic level, TGF alpha prevented deep gastric necrotic lesions and reduced disruption of surface epithelium. Pretreatment with orogastric TGF alpha (200 micrograms/kg) only partially (40%) decreased macroscopic ethanol damage. Intraperitoneal administration of TGF alpha at a dose of 10 micrograms/kg, which does not significantly inhibit gastric acid secretion, decreased aspirin-induced macroscopic damage by > 80%. TGF alpha protection does not seem to be mediated by prostaglandin, glutathione, or ornithine decarboxylase-related events, as evidenced by lack of influence of the inhibition of their production. Pretreatment with the sulfhydryl blocking agent N-ethylmaleimide partially abolished (40%) the protective effect of TGF alpha. In addition, systemic administration of TGF alpha resulted in a two-fold increase in tyrosine phosphorylation of phospholipase C-gamma 1 and in a time- and dose-dependent increase in levels of immunoreactive insoluble gastric mucin; these events occurred in a time frame consistent with their participation in the protective effect of TGF alpha.
D000818:Animals; D001241:Aspirin / Q000633:toxicity; D015232:Dinoprostone / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity; D005033:Ethylmaleimide / Q000494:pharmacology; D005752:Gastric Mucins / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D007213:Indomethacin / Q000494:pharmacology; D008855:Microscopy, Electron, Scanning; D009336:Necrosis; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D005752:Gastric Mucins; D013438:Sulfhydryl Compounds; D016211:Transforming Growth Factor alpha; D019000:Phosphotyrosine; D000431:Ethanol; D014443:Tyrosine; D010738:Type C Phospholipases; D009955:Ornithine Decarboxylase; D015232:Dinoprostone; D005033:Ethylmaleimide; D001241:Aspirin; D007213:Indomethacin