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MUCOSAL BIOLOGY

Cyclooxygenase-2/prostaglandin E₂ accelerates the healing of gastric ulcers via EP₄ receptors

¹Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto; and ²Pharmaceutical Research Laboratories I, Pharmaceutical Research Division Takeda Pharmaceutical, Osaka, Japan

Submitted 19 March 2007 ; accepted in final form 31 July 2007

We examined the involvement of cyclooxygenase (COX)-1 as well as COX-2 in the healing of gastric ulcers and investigated which prostaglandin (PG) EP receptor subtype is responsible for the healing-promoting action of PGE₂. Male SD rats and C57BL/6 mice, including wild-type, COX-1(–/–), and COX-2(–/–), were used. Gastric ulcers were produced by thermocauterization under ether anesthesia. Gastric ulcer healing was significantly delayed in both rats and mice by indomethacin and rofecoxib but not SC-560 given for 14 days after ulceration. The impaired healing was also observed in COX-2(–/–) but not COX-1(–/–) mice. Mucosal PGE₂ content increased after ulceration, and this response was significantly suppressed by indomethacin and rofecoxib but not SC-560. The delayed healing in mice caused by indomethacin was significantly reversed by the coadministration of 11-deoxy-PGE₁ (EP₃/EP₄ agonist) but not other prostanoids, including the EP₁, EP₂, and EP₃ agonists. By contrast, CJ-42794 (selective EP₄ antagonist) significantly delayed the ulcer healing in rats and mice. VEGF expression and angiogenesis were both upregulated in the ulcerated mucosa, and these responses were suppressed by indomethacin, rofocoxib, and CJ-42794. The expression of VEGF in primary rat gastric fibroblasts was increased by PGE₂ or AE1-329 (EP₄ agonist), and these responses were both attenuated by coadministration of CJ-42794. These results confirmed the importance of COX-2/PGE₂ in the healing mechanism of gastric ulcers and further suggested that the healing-promoting action of PGE₂ is mediated by the activation of EP₄ receptors and is associated with VEGF expression.

gastric ulcer; healing; prostaglandin E₂; cyclooxygenase-1 and -2; selective cyclooxygenase-1 and -2 inhibitors; EP₄ antagonist; rat; cyclooxygenase-1 and -2 knockout mice