Department of Pharmacology and Experimental Therapeutics, Division of Pathological Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina (S.H., N.K., A.Y., K.A., K.T.); and General Incorporated Association, Kyoto Research Center for Gastrointestinal Diseases, Karasuma-Oike (K.T.), Kyoto, Japan.
J Pharmacol Exp Ther. 2014 Jun;349(3):470-9. doi: 10.1124/jpet.114.213991. Epub 2014 Apr 8.
Lubiprostone, a bicyclic fatty acid derived from prostaglandin E1, 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 α (TNFα) 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-fluoronaphthalen-1-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/TNFα 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.
利那洛肽是一种源自前列腺素 E1 的双环脂肪酸，已被用于治疗慢性便秘和肠易激综合征，其作用机制归因于通过激活氯离子通道蛋白 2/囊性纤维化跨膜转导调节因子（ClC-2/CFTR）氯离子通道刺激肠道液分泌。我们研究了利那洛肽对消炎痛诱导的肠病的影响，并探讨了所涉及的功能机制，包括其与 EP4 受体亚型的关系。雄性 Sprague-Dawley 大鼠给予消炎痛（10 mg/kg p.o.），24 小时后处死，以检查小肠发生的出血性病变。利那洛肽（0.01-1 mg/kg）口服给药，在消炎痛处理前 30 分钟和 9 小时后两次给药。消炎痛显著损伤小肠，伴有肠道蠕动过度、粘液和液体分泌减少以及肠杆菌入侵增加，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。利那洛肽显著减轻了这些病变的严重程度，并同时抑制了功能变化。AE3-208[4-（4-氰基-2-（2-（4-氟萘-1-基）丙酰基氨基）苯基）丁基]酸，一种选择性 EP4 拮抗剂，与 CFTR（inh）-172[CFTR 抑制剂]共同给药可显著阻断利那洛肽对肠病变和功能改变的作用。这些结果表明，利那洛肽可能通过 EP4 受体依赖性机制预防消炎痛诱导的肠病。这种作用可能与抑制肠道蠕动过度和粘液/液体分泌增加有关，从而抑制细菌入侵和 iNOS/TNFα 表达，这是肠病的主要发病事件。ClC-2 氯离子通道的直接激活不太可能导致利那洛肽的保护作用。
