Cyclooxygenase-2/prostaglandin E2 accelerates the healing of gastric ulcers via EP4 receptors
Cyclooxygenase-2/prostaglandin E2 accelerates the healing of gastric ulcers via EP4 receptors
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DOI：
10.1152/ajpgi.00131.2007
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发表时间：
2007-10-01
影响因子：
4.5
通讯作者：
Takeuchi, Koji
中科院分区：
文献类型：
--
作者：
Hatazawa, Ryo;Tanaka, Akiko;Takeuchi, Koji
环氧合酶-2/前列腺素E-2通过EP4受体加速胃溃疡愈合。Am J Physiol胃肠病肝生理学293：G788-G797,2007。2007年8月2日首次出版；DOI：10.1152/ajpgi.00131.2007。-我们研究了环氧合酶(COX)-1和COX-2在胃溃疡愈合中的作用，并调查了前列腺素(PG)EP受体亚型负责前列腺素E的促进愈合作用(2)。实验选用雄性SD大鼠和C57BL/6小鼠，包括野生型、COX-1(-/-)和COX-2(-/-)。乙醚麻醉下热灼烧法造成胃溃疡。在大鼠和小鼠的胃溃疡愈合过程中，消炎痛和罗非昔布均显着延迟愈合，而SC-560在溃疡后14天给药则无明显影响。在COX-2(-/-)小鼠中也观察到愈合受损，但在COX-1(-/-)小鼠中没有观察到。溃疡后粘膜PGE(2)含量增加，消炎痛和罗非昔布可显著抑制这一反应，但SC-560不能。联合应用11-脱氧前列腺素E(1)(EP3/EP4激动剂)可显著逆转消炎痛引起的小鼠愈合延迟，但不能逆转其他前列腺素类药物，包括EP1、EP2和EP3激动剂。相反，选择性EP4拮抗剂CJ-42794显著延缓了大鼠和小鼠的溃疡愈合。溃疡黏膜中血管内皮生长因子表达和血管生成均上调，这些反应可被消炎痛、罗福昔布和CJ-42794抑制。前列腺素E(2)或EP4激动剂AE1329可增强原代培养的大鼠胃成纤维细胞血管内皮细胞生长因子的表达，CJ-42794可减弱这两种作用。这些结果证实了COX-2/PGE(2)在胃溃疡愈合机制中的重要性，并进一步提示PGE(2)的促愈合作用是通过激活EP4受体而实现的，并与血管内皮生长因子的表达有关。
Cyclooxygenase-2/prostaglandin E-2 accelerates the healing of gastric ulcers via EP4 receptors. Am J Physiol Gastrointest Liver Physiol 293: G788-G797, 2007. First published August 2, 2007; doi:10.1152/ajpgi.00131.2007.-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 PGE(2). 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 PGE(2) 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-PGE(1) (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 PGE(2) or AE1-329 (EP4 agonist), and these responses were both attenuated by coadministration of CJ-42794. These results confirmed the importance of COX-2/PGE(2) in the healing mechanism of gastric ulcers and further suggested that the healing-promoting action of PGE(2) is mediated by the activation of EP4 receptors and is associated with VEGF expression.