Submitted on March 19, 2007
Accepted on July 31, 2007
Cyclooxygenase-2/Prostaglandin E2 Accelerates the Healing of Gastric Ulcers Via EP4 Receptors
Ryo Hatazawa1, Akiko Tanaka1, Mayu Tanigami1, Kikuko Amagase1, SHINICHI KATO2, Yasuko Ashida3, and Koji Takeuchi1*
1 Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Kyoto, Japan
2 Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, 607-8414, Japan; Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Kyoto, Japan
3 Pharmaceutical Research Laboratories I., Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Osaka, Osaka, Japan
* To whom correspondence should be addressed. E-mail: takeuchi{at}mb.kyoto-phu.ac.jp.
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 C57/BL6 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 co-administration of 11-deoxy PGE1 (EP3/EP4 agonist), but not other prostanoids, including the EP1, EP2 and EP3 agonists. By contrast, CJ42794 (selective EP4 antagonist) significantly delayed the ulcer healing in rats and mice. VEGF expression and angiogenesis were both up-regulated in the ulcerated mucosa, and these responses were suppressed by indomethacin, rofocoxib and CJ42794. 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 co-administration of CJ42794. 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 associated with VEGF expression.
