Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 chloride channel, lubiprostone
Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 chloride channel, lubiprostone
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DOI：
10.1152/ajpgi.00183.2006
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发表时间：
2007-02-01
影响因子：
4.5
通讯作者：
Blikslager, Anthony T.
中科院分区：
文献类型：
--
作者：
Moeser, Adam J.;Nighot, Prashant K.;Blikslager, Anthony T.
先前利用肠道缺血损伤的离体猪模型进行的研究表明，前列腺素（PG）E2通过一种涉及氯离子（Cl⁻）分泌以及细胞旁通透性降低的机制刺激黏膜屏障功能的修复。进一步的实验显示，PGE₂诱导的黏膜修复的信号传导机制是通过2型氯离子通道（ClC - 2）介导的。因此，本研究的目的是通过评估用选择性ClC - 2激动剂鲁比前列酮处理的缺血损伤肠道黏膜的修复情况，直接研究ClC - 2在黏膜修复中的作用。将缺血损伤的猪回肠黏膜置于尤斯灌流室中，测量对鲁比前列酮的反应所产生的短路电流（Iₛₑ）和跨上皮电阻（TER）。将0.01 - 1 μM的鲁比前列酮应用于缺血损伤的黏膜，可诱导TER呈浓度依赖性增加，1 μM的鲁比前列酮可使TER增加两倍（ΔTER = 26Ω·cm²；P < 0.01）。然而，与非选择性分泌激动剂PGE₂（1 μM）相比，尽管鲁比前列酮（1 μM）引起的Iₛₑ反应较低，但它能使TER升高得更多。此外，鲁比前列酮显著（P < 0.05）降低了³H标记的甘露醇从黏膜到浆膜的通量，使其达到与正常对照组织相当的水平，并使紧密连接蛋白恢复到紧密连接部位。用选择性激动剂鲁比前列酮激活ClC - 2可刺激缺血损伤肠道的TER升高以及甘露醇通量降低，同时伴有紧密连接的结构变化。与前列腺素（如PGE₂）的非选择性作用相比，像鲁比前列酮这样的前列酮类药物可能为加速急性损伤肠道的恢复提供一种选择性的新型药理机制。
Previous studies utilizing an ex vivo porcine model of intestinal ischemic injury demonstrated that prostaglandin ( PG) E2 stimulates repair of mucosal barrier function via a mechanism involving Cl- secretion and reductions in paracellular permeability. Further experiments revealed that the signaling mechanism for PGE(2)-induced mucosal recovery was mediated via type-2 Cl- channels (ClC-2). Therefore, the objective of the present study was to directly investigate the role of ClC-2 in mucosal repair by evaluating mucosal recovery in ischemia-injured intestinal mucosa treated with the selective ClC-2 agonist lubiprostone. Ischemia-injured porcine ileal mucosa was mounted in Ussing chambers, and short-circuit current (I-sc) and transepithelial electrical resistance ( TER) were measured in response to lubiprostone. Application of 0.01 - 1 mu M lubiprostone to ischemia-injured mucosa induced concentration-dependent increases in TER, with 1 mu M lubiprostone stimulating a twofold increase in TER ( Delta TER = 26 Omega center dot cm(2); P < 0.01). However, lubiprostone ( 1 mu M) stimulated higher elevations in TER despite lower Isc responses compared with the nonselective secretory agonist PGE(2) ( 1 mu M). Furthermore, lubiprostone significantly ( P < 0.05) reduced mucosal- to-serosal fluxes of H-3-labeled mannitol to levels comparable to those of normal control tissues and restored occludin localization to tight junctions. Activation of ClC-2 with the selective agonist lubiprostone stimulated elevations in TER and reductions in mannitol flux in ischemia- injured intestine associated with structural changes in tight junctions. Prostones such as lubiprostone may provide a selective and novel pharmacological mechanism of accelerating recovery of acutely injured intestine compared with the nonselective action of prostaglandins such as PGE(2).