Cyclooxygenase-2/prostaglandin E2 accelerates the healing of gastric ulcers via EP4 receptors.
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 EP(4) 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.
Dept. of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical Univ., Misasagi, Yamashina, Kyoto 607, Japan.
Ryo
R
Hatazawa
Akiko
A
Tanaka
Mayu
M
Tanigami
Kikuko
K
Amagase
Shinichi
S
Kato
Yasuko
Y
Ashida
Koji
K
Takeuchi
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000502:physiology*; D015232:Dinoprostone / Q000502:physiology*; D007783:Lactones / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013276:Stomach Ulcer / Q000188:drug therapy*; D013450:Sulfones / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D014945:Wound Healing / Q000502:physiology*
C523467:(S)-4-(1-(5-chloro-2-(4-fluorophenyoxy) benzamido)ethyl) benzoic acid; D001549:Benzamides; D001565:Benzoates; D007783:Lactones; C545651:Ptger4 protein, mouse; C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; C116926:rofecoxib; D005576:Colforsin; D003994:Bucladesine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone