Activation of Intestinal Cl- Secretion by Lubiprostone Requires the Cystic Fibrosis Transmembrane Conductance Regulator
Activation of Intestinal Cl- Secretion by Lubiprostone Requires the Cystic Fibrosis Transmembrane Conductance Regulator
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DOI：
10.1053/j.gastro.2009.05.037
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发表时间：
2009-09-01
期刊：
影响因子：
29.4
通讯作者：
de Jonge, Hugo R.
中科院分区：
文献类型：
--
作者：
Bijvelds, Marcel J. C.;Bot, Alice G. M.;de Jonge, Hugo R.
背景与目的：鲁比前列酮通过刺激肠液分泌来缓解便秘，据称是通过激活ClC-2型Cl-通道。肠梗阻也是囊性纤维化（CF）患者痛苦的复发原因，其由CF跨膜传导调节器（CFTR）Cl-通道活性的丧失引起。由于ClC-2募集可能对CF患者有益，我们研究了鲁比前列酮的作用方式。方法：在3个模型系统中，在Ussing室中测量Cl-转运：（1）T84结肠细胞，（2）野生型和CF小鼠的肠上皮，以及（3）CF患者和对照的肠上皮。结果：在T84细胞单层中，鲁比前列酮诱导了强分泌反应。基底外侧质膜的选择性透化显示鲁比前列酮激活顶端Cl-传导。鲁比前列酮反应被H89（cAMP依赖性蛋白激酶的抑制剂）减弱，鲁比前列酮阻止了对cAMP激动剂毛喉素的反应。CFTRinh 172阻断CFTR，而CdCl 2不阻断ClC-2，抑制鲁比前列酮反应。鲁比前列酮在小鼠肠道中诱导CdCl 2不敏感的分泌反应，但在Cftr缺失小鼠中未能诱导肠道Cl-分泌。相应地，鲁比前列酮在人肠上皮中诱导分泌反应，但在CF患者的组织中不诱导。在研究的所有3种模型中，EP 4型前列腺素受体拮抗剂L-161，982阻断了鲁比前列酮反应。在T84细胞中，鲁比前列酮诱导对EP 4受体阻断敏感的cAMP水平升高。结论：鲁比前列酮通过前列腺素受体信号传导增强肠道Cl-和液体分泌，触发CFTR激活。因此，其用于治疗CF相关肠道疾病的用途有限。
BACKGROUND & AIMS: Lubiprostone alleviates constipation by stimulating intestinal fluid secretion, purportedly through activation of ClC-2-type Cl- channels. intestinal obstruction is also a recurrent cause of distress in cystic fibrosis (CF) patients, caused by loss of CF transmembrane conductance regulator (CFTR) Cl- channel activity. Because ClC-2 recruitment might be beneficial to CF patients, we investigated lubiprostone's mode of action. METHODS: Cl- transport was measured in an Ussing chamber, in 3 model systems: (1) T84 colonocytes, (2) intestinal epithelium of wild-type and CF mice, and (3) intestinal epithelium of CF patients and controls. RESULTS: In T84 monolayers, lubiprostone induced a robust secretory response. Selective permeabilization of the basolateral plasma membrane revealed that lubiprostone activated an apical Cl- conductance. The lubiprostone response was attenuated by H89, an inhibitor of the cAMP-dependent protein kinase, and lubiprostone precluded responsiveness to the cAMP agonist forskolin. CFTR blockage by CFTRinh172, but not ClC-2 blockage by CdCl2, inhibited the lubiprostone response. Lubiprostone induced a CdCl2-insensitive secretory response in mouse intestine, but failed to induce intestinal Cl- secretion in Cftr-null mice. Correspondingly, lubiprostone induced a secretory response in human intestinal epithelium, but not in tissue of CF patients. The EP4-type prostanoid receptor antagonist L-161,982 blocked the lubiprostone response in all 3 models studied. In T84 cells, lubiprostone induced a rise in cAMP levels that was sensitive to EP4-receptor blockage. CONCLUSIONS: Lubiprostone enhances intestinal Cl- and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. Therefore, it is of limited use for treatment of CF-related intestinal disease.