Epidermal growth factor modulates pepsinogen secretion in guinea pig gastric chief cells.
OBJECTIVE
Although epidermal growth factor (EGF) inhibits gastric acid secretion, the effects it exerts on gastric chief cells are unknown. The aim of this study was to investigate whether EGF modulates pepsinogen release and intracellular Ca2+ concentrations ([Ca2+]i) and whether the effect involves mitogen-activated protein (MAP) kinase, 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 by the NO coproduct citrulline.


RESULTS
In situ hybridization, immunohistochemistry, and immunoblotting showed that EGF receptor and MAP kinases were constitutively expressed in chief cells. EGF caused a concentration-dependent stimulation of pepsinogen secretion and MAP kinase activity and determined a 2.5-7.0-fold increase in [Ca2+]i, inositol 1,4,5-tryphosphate, prostaglandin E2, and leukotriene B4. Tyrosine kinase inhibitors and cyclooxygenase and lipoxygenase inhibitors reduced pepsinogen secretion and eicosanoid generation induced by EGF. EGF increased citrulline generation and guanosine 3',5'-cyclic monophosphate accumulation sixfold; the effect was blocked by NG monomethyl-L-arginine, which is an NO synthase inhibitor.


CONCLUSIONS
EGF stimulates pepsinogen secretion by activating eicosanoid generation, tyrosine kinases, MAP kinases, Ca2+, NO, and guanosine 3',5'-cyclic monophosphate.
Fiorucci
S
S
Dipartimento di Medicina Clinica, Patologia e Farmacologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, Perugia, Italy.
Lanfrancone
L
L
Santucci
L
L
Calabro
A
A
Orsini
B
B
Federici
B
B
Morelli
A
A
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000032:analysis; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D010435:Pepsinogens / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism
D010435:Pepsinogens; D009569:Nitric Oxide; D004815:Epidermal Growth Factor; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D015544:Inositol 1,4,5-Trisphosphate; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000252:Calcium-Transporting ATPases; D006152:Cyclic GMP; D002118:Calcium; D013936:Thymidine