Roles of cyclooxygenase-2 and prostacyclin/IP receptors in mucosal defense against ischemia/reperfusion injury in mouse stomach.
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 E(2) (EP)1, EP3, or prostaglandin I(2) (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-PGF(1alpha) and PGE(2) 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 (PGI(2)) analog, significantly prevented the I/R-induced gastric lesions in the absence and presence of indomethacin or rofecoxib. PGE(2) 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 PGI(2) through the activation of IP receptors.
Kotani
Tohru
T
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Japan.
Kobata
Atsushi
A
Nakamura
Eiji
E
Amagase
Kikuko
K
Takeuchi
Koji
K
D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044006:Receptors, Epoprostenol / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000150:complications* / Q000473:pathology; D013276:Stomach Ulcer / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
D016861:Cyclooxygenase Inhibitors; D044006:Receptors, Epoprostenol; D051546:Cyclooxygenase 2