Expression of cyclooxygenase (COX)-1 and COX-2 in adaptive cytoprotection induced by mild stress

Prostaglandins (PG) derived from COX-1 play an important role in the mainte nance of mucosal integrity but the role of COX-2-derived products in mucosa l defence mechanism has not been fully explained. Mild stress is known to p revent gastric mucosal lesions induced by severe stress via the phenomenon of adaptive cytoprotection but it remains unknown which COX is involved in this adaptation. In this study, the mucosal expression of COX-I and COX-2 w as examined and the inhibitors of these enzymes were used to determine the contribution of these enzymes in adaptive cytoprotection induced by mild st ress. Male Wistar rats were exposed to mild water immersion and restraint s tress (WRS) at various time intervals ranging from 5 min up to 2 h followed 1 h later by exposure to severe 3.5 h WRS with or without pretreatment wit h: 1) NS-398 (10 mg.kg(-1) i.g.), a selective COX-2 inhibitor; 2) resveratr ol (5 mg.kg(-1) i.g.), a selective COX 1 inhibitor; 3) meloxicam (2 mg.kg(- 1) i.g.), preferential COX-2 inhibitor; and 4) indomethacin (5 mg.kg(-1) i. p), non-selective inhibitor of COX. The number of WRS lesions was counted, gastric blood flow (GBF) was measured by H-2-gas clearance technique, mucos al biopsy samples were taken for the assessment of PGE(2) by radioimmunoass ay, and the expression of COX-1 and COX-2 mRNA by RT-PCR. WRS for 3.5 h pro duced numerous gastric lesions, decreased GBF by 48% and inhibited formatio n of PGE(2) by 68% as compared to intact mucose. Exposure to mild WRS durin g 5-30 min by itself failed to affect mucosal integrity but significantly a ttenuated gastric lesions induced by exposure to severe 3.5 h stress; the m aximal protective effect being achieved with mild WRS during 15 min. This p rotective effect was accompanied by the rise in GBF and the generation of P GE(2) in the gastric mucosa. After extension of mild WRS from 15 min up to 1 or 2 h before more severe 3.5 h WRS, the loss of cytoprotective effect of mild WRS against severe stress accompanied by significant fall in the GBF were observed. Pretreatment with NS-398 (10 mg.kg(-1) i.g.) that failed to affect mucosal PGE(2) generation, reduced significantly the protection and accompanying rise in GBF produced by mild WRS whereas resveratrol partly re duced the protection and the rise in GBF induced by mild WRS. Meloxicam or indomethacin significantly inhibited PGE(2) generation and completely aboli shed the hyperemia and protection induced by mild WRS against more severe s tress. The protective and hyperemic effects of mild WRS were completely res tored by the addition of 16,16 dm PGE(2) (5 mu g.kg(-1) i.g.) to NS-398 or resveratrol, while the deleterious effects of meloxicam and indomethacin we re significantly attenuated by the concomitant treatment with this PGE(2) a nalogue. We conclude that PC derived from both, COX-1 and COX-2 appear to b e involved in adaptive cytoprotection developed in response to mild stresso rs. (C) 2000 Elsevier Science Ltd. Published by Editions scientifiques et m edicales Elsevier SAS.