Importance of cyclooxygenase-1/prostacyclin in modulating gastric mucosal integrity under stress conditions

Background and AimWe investigated the roles of cyclooxygenase (COX) isozymes and prostaglandins (PGs) and their receptors in mucosal defense against cold-restraint stress (CRS)-induced gastric lesions. MethodsMale C57BL/6 wild-type (WT) mice and those lacking COX-1 or COX-2 as well as those lacking EP1, EP3, or IP receptors were used after 18h fasting. Animals were restrained in Bollman cages and kept in a cold room at 10 degrees C for 90min. ResultsCRS induced multiple hemorrhagic lesions in WT mouse stomachs. The severity of these lesions was significantly worsened by pretreatment with the nonselective COX inhibitors (indomethacin, loxoprofen) or selective COX-1 inhibitor (SC-560), while neither of the selective COX-2 inhibitors (rofecoxib and celecoxib) had any effect. These lesions were also aggravated in animals lacking COX-1, but not COX-2. The expression of COX-2mRNA was not detected in the stomach after CRS, while COX-1 expression was observed under normal and stressed conditions. The gastric ulcerogenic response to CRS was similar between EP1 or EP3 knockout mice and WT mice, but was markedly worsened in animals lacking IP receptors. Pretreating WT mice with iloprost (the PGI(2) analog) significantly prevented CRS-induced gastric lesions in the presence of indomethacin. PGE(2) also reduced the severity of these lesions, and the effect was mimicked by the EP4 agonist, AE1-329. ConclusionsThese results suggest that endogenous PGs derived from COX-1 play a crucial role in gastric mucosal defense during CRS, and this action is mainly mediated by PGI(2)/IP receptors and partly by PGE(2)/EP4 receptors.