ACTIVATION OF GENES FOR GROWTH-FACTORS AND CYCLOOXYGENASES IN RAT GASTRIC-MUCOSA DURING RECOVERY FROM STRESS DAMAGE

Growth factors and prostaglandins protect the gastric mucosa against s tress-induced lesions but their role in the recovery of the mucosa fro m these lesions has been little studied. We evaluated gastric mucosa l esions, gastric blood flow, mucosal generation of prostaglandin E-2 an d mucosal gene expression of epidermal growth factor (EGF) and transfo rming growth factor alpha (TGF alpha) as well as constitutive prostagl andin cyclooxygenase-1 and inducible cyclooxygenase-2 and the effect o f the inhibition of these enzymes on the recovery of mucosa from the s tress-induced lesions. Rats were: exposed to 3.5 h of water immersion and restraint stress and killed at 0, 2, 4, 6, 8, 12 and 24 h after st ress. The number of gastric lesions was determined and gastric blood f low was measured by H-2-gas clearance. Gastric acid secretion was test ed in separate gastric fistula rats. Gastric mucosa biopsies were take n for determination of immunoreactive EGF and TGF alpha. Expression of EGF and TGF alpha mRNA and cyclooxygenase-1 and cyclooxygenase-2 mRNA was also determined by reverse-transcriptase polymerase chain reactio n. The number of gastric lesions induced by 3.5 h stress averaged simi lar to 20 per rat and declined significantly at 2, 4, 6, 8 and 12 h, t o disappear almost completely after 24 h. This was accompanied by a gr adual rise in gastric blood flow, mucosal generation of prostaglandin E-2 and mucosal EGF and TGF alpha contents, while the increased gastri c acid secretion returned to normal. In the intact mucosa, EGF mRNA wa s not detected but TGF alpha mRNA was found in measurable amounts. Fol lowing exposure to stress, the expression of both these factors was si gnificantly increased. Similarly, the expression of cyclo-oxygenase-1 and cycloosygenase-2 mRNA was detected in the oxyntic mucosa at all ti me intervals after exposure to stress. Indomethacin (5 mg/kg i.p.), an inhibitor of cyclooxygenase-1 and cyclooxygenase-2, and moloxicam (1 mg/kg i.p.), an inhibitor of cyclooxygenase-2, both prolonged the heal ing of stress lesions and reduced the gastric blood flow, while enhanc ing,gastric acid secretion at all times tested. We conclude that heali ng of stress lesions results in the restoration gastric blood flow and mucosal prostaglandin generation and that these effects are accompani ed by overexpression of EGF and TGF alpha as well as cyclooxygenase-1 and cyclooxygenase-2 mRNA and by increased biosynthesis of gastroprote ctive prostaglandin. (C) 1998 Elsevier Science B.V.