Lubiprostone Prevents Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Damage by Suppressing the Expression of Inflammatory Mediators via EP4
Lubiprostone Prevents Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Damage by Suppressing the Expression of Inflammatory Mediators via EP4
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DOI：
10.1124/jpet.114.213991
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发表时间：
2014-06-01
影响因子：
3.5
通讯作者：
Takeuchi, Koji
中科院分区：
文献类型：
--
作者：
Hayashi, Shusaku;Kurata, Naoto;Takeuchi, Koji
鲁比前列酮是一种源自前列腺素E - 1的双环脂肪酸，已被用于治疗慢性便秘和肠易激综合征，其作用机制被认为是通过激活氯离子通道蛋白2/囊性纤维化跨膜传导调节因子（ClC - 2/CFTR）氯离子通道来刺激肠道液体分泌。我们研究了鲁比前列酮对吲哚美辛诱导的肠病的影响，并探讨了相关的作用机制，包括它与EP4受体亚型的关系。雄性斯普拉格 - 道利大鼠给予吲哚美辛（10 mg/kg，口服），24小时后处死，以检查小肠出现的出血性病变。鲁比前列酮（0.01 - 1 mg/kg）在吲哚美辛处理前30分钟和处理后9小时口服给药两次。吲哚美辛显著损伤小肠，伴有肠道运动亢进、黏液和液体分泌减少、肠道细菌入侵增加以及诱导型一氧化氮合酶（iNOS）和肿瘤坏死因子α（TNFα）mRNA的上调。鲁比前列酮显著减轻了这些病变的严重程度，同时抑制了功能变化。选择性EP4拮抗剂AE3 - 208[4 -（4 - 氰基 - 2 -（2 -（4 - 氟萘 - 1 - 基）丙酰氨基）苯基）丁酸]与鲁比前列酮共同给药可显著消除鲁比前列酮对肠道病变和功能改变的作用，但CFTR抑制剂CFTR(inh)-172则不能。这些结果表明，鲁比前列酮可能通过一种依赖EP4受体的机制预防吲哚美辛诱导的肠病。这种作用可能在功能上与抑制肠道运动亢进以及增加黏液/液体分泌有关，从而抑制细菌入侵和iNOS/TNFα表达，这些都是肠病中的主要致病事件。CFTR/ClC - 2氯离子通道的直接激活不太可能对鲁比前列酮的保护作用有贡献。
Lubiprostone, a bicyclic fatty acid derived from prostaglandin E-1, has been used to treat chronic constipation and irritable bowel syndrome, and its mechanism of action has been attributed to the stimulation of intestinal fluid secretion via the activation of the chloride channel protein 2/cystic fibrosis transmembrane regulator (ClC-2/CFTR) chloride channels. We examined the effects of lubiprostone on indomethacin-induced enteropathy and investigated the functional mechanisms involved, including its relationship with the EP4 receptor subtype. Male Sprague-Dawley rats were administered indomethacin (10 mg/kg p.o.) and killed 24 hours later to examine the hemorrhagic lesions that developed in the small intestine. Lubiprostone (0.01-1 mg/kg) was administered orally twice 30 minutes before and 9 h after the indomethacin treatment. Indomethacin markedly damaged the small intestine, accompanied by intestinal hypermotility, a decrease in mucus and fluid secretion, and an increase in enterobacterial invasion as well as the up-regulation of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor a (TNF alpha) mRNAs. Lubiprostone significantly reduced the severity of these lesions, with the concomitant suppression of the functional changes. The effects of lubiprostone on the intestinal lesions and functional alterations were significantly abrogated by the coadministration of AE3-208 [4-(4-cyano-2-(2-(4-fluoronaphthalen1- yl) propionylamino) phenyl) butyric acid], a selective EP4 antagonist, but not by CFTR(inh)-172, a CFTR inhibitor. These results suggest that lubiprostone may prevent indomethacin-induced enteropathy via an EP4 receptor-dependent mechanism. This effect may be functionally associated with the inhibition of intestinal hypermotility and increase in mucus/fluid secretion, resulting in the suppression of bacterial invasion and iNOS/ TNFa expression, which are major pathogenic events in enteropathy. The direct activation of CFTR/ClC-2 chloride channels is not likely to have contributed to the protective effects of lubiprostone.