EPIDERMAL GROWTH-FACTOR MODULATES PEPSINOGEN SECRETION IN GUINEA-PIG GASTRIC CHIEF CELLS

Background & Aims: Although epidermal growth factor (EGF) inhibits gas tric acid secretion, the effects it exerts on gastric chief cells are unknown, The aim of this study was to investigate whether EGF modulate s pepsinogen release and intracellular Ca2+ concentrations ([Ca2+](i)) and whether the effect involves mitogen-activated protein (MAP) kinas e, eicosanoid generation, and nitric oxide. Methods: Chief cells were obtained by sequential digestion with collagenase and Ca2+ chelation. [Ca2+](i) was measured in cells loaded with Fura-2 and NO generation b y the NO coproduct citrulline, Results: In situ hybridization, immunoh istochemistry, and immunoblotting showed that EGF receptor and MAP kin ases were constitutively expressed in chief cells, EGF caused a concen tration-dependent stimulation of pepsinogen secretion and MAP kinase a ctivity and determined a 2.5 - 7.0-fold increase in [Ca2+](i), inosito l 1,4,5-tryphosphate, prostaglandin E(2), and leukotriene B-4. Tyrosin e kinase inhibitors and cyclooxygenase and lipoxygenase inhibitors red uced pepsinogen secretion and eicosanoid generation induced by EGF. EG F increased citrulline generation and guanosine 3',5'-cyclic monophosp hate accumulation sixfold; the effect was blocked by N-G monomethyl-L- arginine, which is an NO synthase inhibitor, Conclusions: EGF stimulat es pepsinogen secretion by activating eicosanoid generation, tyrosine kinases, MAP kinases, Ca2+, NO, and guanosine 3',5'-cyclic monophospha te.