Hatazawa Ryo, Tanaka Akiko, Tanigami Mayu, Amagase Kikuko, Kato Shinichi, Ashida Yasuko, Takeuchi Koji
Dept. of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical Univ., Misasagi, Yamashina, Kyoto 607, Japan.
Am J Physiol Gastrointest Liver Physiol. 2007 Oct;293(4):G788-97. doi: 10.1152/ajpgi.00131.2007. Epub 2007 Aug 2.
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.
我们研究了环氧化酶（COX）-1和COX-2在胃溃疡愈合中的作用，并调查了哪种前列腺素（PG）EP受体亚型介导了PGE2的促愈合作用。使用了雄性SD大鼠和C57BL/6小鼠，包括野生型、COX-1基因敲除型（COX-1(-/-)）和COX-2基因敲除型（COX-2(-/-)）。在乙醚麻醉下通过热烧灼法制造胃溃疡。溃疡形成后给予消炎痛、罗非昔布14天，大鼠和小鼠的胃溃疡愈合均显著延迟，但给予SC-560则无此现象。在COX-2(-/-)小鼠中也观察到愈合受损，但COX-1(-/-)小鼠未出现。溃疡形成后黏膜PGE2含量增加，消炎痛和罗非昔布可显著抑制这一反应，但SC-560无此作用。消炎痛导致的小鼠愈合延迟可通过同时给予11-脱氧-PGE1（EP3/EP4激动剂）显著逆转，但其他前列腺素，包括EP1、EP2和EP3激动剂则无此作用。相比之下，CJ-42794（选择性EP(4)拮抗剂）可显著延迟大鼠和小鼠的溃疡愈合。溃疡黏膜中的VEGF表达和血管生成均上调，消炎痛、罗非昔布和CJ-42794可抑制这些反应。PGE2或AE1-329（EP4激动剂）可增加原代大鼠胃成纤维细胞中VEGF的表达，同时给予CJ-42794可减弱这两种反应。这些结果证实了COX-2/PGE2在胃溃疡愈合机制中的重要性，并进一步表明PGE2的促愈合作用是由EP4受体激活介导的，且与VEGF表达有关。
