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 stress-induced lesions but their role in the recovery of the mucosa from these lesions has been little studied. We evaluated gastric mucosa lesions, gastric blood flow, mucosal generation of prostaglandin E2 and mucosal gene expression of epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) as well as constitutive prostaglandin cyclooxygenase-1 and inducible cyclooxygenase-2 and the effect of the inhibition of these enzymes on the recovery of mucosa from the stress-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 stress. The number of gastric lesions was determined and gastric blood flow was measured by H2-gas clearance. Gastric acid secretion was tested in separate gastric fistula rats. Gastric mucosa biopsies were taken 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 reaction. The number of gastric lesions induced by 3.5 h stress averaged approximately 20 per rat and declined significantly at 2, 4, 6, 8 and 12 h, to disappear almost completely after 24 h. This was accompanied by a gradual rise in gastric blood flow, mucosal generation of prostaglandin E2 and mucosal EGF and TGF alpha contents, while the increased gastric acid secretion returned to normal. In the intact mucosa, EGF mRNA was not detected but TGF alpha mRNA was found in measurable amounts. Following exposure to stress, the expression of both these factors was significantly increased. Similarly, the expression of cyclo-oxygenase-1 and cyclooxygenase-2 mRNA was detected in the oxyntic mucosa at all time intervals after exposure to stress. Indomethacin (5 mg/kg i.p.), an inhibitor of cyclooxygenase-1 and cyclooxygenase-2, and meloxicam (1 mg/kg i.p.), an inhibitor of cyclooxygenase-2, both prolonged the healing of stress lesions and reduced the gastric blood flow, while enhancing gastric acid secretion at all times tested. We conclude that healing of stress lesions results in the restoration gastric blood flow and mucosal prostaglandin generation and that these effects are accompanied by overexpression of EGF and TGF alpha as well as cyclooxygenase-1 and cyclooxygenase-2 mRNA and by increased biosynthesis of gastroprotective prostaglandin.