Abstract
We examined the roles of cyclooxygenase (COX) isozymes, prostaglandins (PGs), and their receptors in the mucosal defense against ischemia/reperfusion (I/R)-induced gastric lesions in mice. Male C57BL/6 mice, including wild-type animals and those lacking prostaglandin E2 (EP)1, EP3, or prostaglandin I2 (IP) receptors, were used after 18 h of fasting. Under urethane anesthesia, the celiac artery was clamped (ischemia) for 30 min, and then reperfusion was achieved for 60 min through the removal of the clamp, and the stomach was examined for lesions. I/R produced hemorrhagic gastric lesions in wild-type mice. The severity of lesions was significantly increased by pretreatment with indomethacin (a nonselective COX inhibitor) and rofecoxib (a selective COX-2 inhibitor) but not 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560; a selective COX-1 inhibitor). The expression of COX-2 mRNA was up-regulated in the stomach following I/R but not by sham operation or ischemia alone. The ulcerogenic response was markedly aggravated in IP receptor knockout mice but not those lacking EP1 or EP3 receptors. I/R increased the levels of 6-keto-PGF1α and PGE2 in the stomach of wild-type mice, and this response was attenuated by indomethacin and rofecoxib but not SC-560. Pretreatment of wild-type mice with iloprost, a prostacyclin (PGI2) analog, significantly prevented the I/R-induced gastric lesions in the absence and presence of indomethacin or rofecoxib. PGE2 also reduced the severity of I/R-induced gastric lesions, yet the effect was much less pronounced than that of iloprost. These results suggest that endogenous PGs derived from COX-2 play a crucial role in gastric mucosal defense during I/R, and this action is mainly mediated by PGI2 through the activation of IP receptors.
Footnotes
-
This research was supported in part by the Kyoto Pharmaceutical University's “21st Century COE” program and the “Open Research” Program from the Ministry of Education, Science and Culture of Japan.
-
doi:10.1124/jpet.105.093195.
-
ABBREVIATIONS: I/R, ischemia/reperfusion; COX, cyclooxygenase; PG, prostaglandin; EP, prostaglandin E2 receptor; PGI2, prostacyclin; IP, prostaglandin I2 receptor; MPO, myeloperoxidase; PCR, polymerase chain reaction; SC-560, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; NS-398, N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide; DFU, 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methyl sulfonyl)phenyl-2(5II)-furanone.
- Received July 24, 2005.
- Accepted October 17, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|