TRANSFORMING GROWTH FACTOR-ALPHA PROTECTION AGAINST DRUG-INDUCED INJURY TO THE RAT GASTRIC-MUCOSA INVIVO

This study was designed to determine whether transforming growth factor alpha (TGFalpha) protects rat gastric mucosa against ethanol- and aspirin-induced injury. Systemic administration of TGFalpha dose-dependently decreased 100% ethanol-induced gastric mucosal injury; a dose of 50 mug/kg delivered intraperitoneally 15 min before ethanol decreased macroscopic mucosal injury by > 90%. At the microscopic level, TGFalpha prevented deep gastric necrotic lesions and reduced disruption of surface epithelium. Pretreatment with orogastric TGFalpha (200 mug/kg) only partially (40%) decreased macroscopic ethanol damage. Intraperitoneal administration of TGFalpha at a dose of 10 mug/kg, which does not significantly inhibit gastric acid secretion, decreased aspirin-induced macroscopic damage by > 80%. TGFalpha 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 TGFalpha. In addition, systemic administration of TGFalpha 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 TGFalpha.