Bile acids stimulate chloride secretion through CFTR and calcium-activated Cl- channels in Calu-3 airway epithelial cells
Bile acids stimulate chloride secretion through CFTR and calcium-activated Cl- channels in Calu-3 airway epithelial cells
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DOI：
10.1152/ajplung.00352.2013
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发表时间：
2014-09-01
影响因子：
4.9
通讯作者：
Harvey, Brian J.
中科院分区：
文献类型：
--
作者：
Hendrick, Siobhan M.;Mroz, Magdalena S.;Harvey, Brian J.
由胃食管反流物吸入引起的胆汁酸通常存在于囊性纤维化和其他呼吸窘迫疾病患者的下呼吸道中。令人惊讶的是，很少或没有关于胆汁酸调节气道上皮离子转运的信息。各种共轭和非共轭二级胆汁酸的分泌效果进行了研究，在Calu-3气道上皮细胞生长下的气液界面和安装在Ussing室。以短路电流（I-sc）测量产电跨上皮离子转运。牛磺酸结合的二级胆汁酸，牛磺脱氧胆酸（TDCA），被认为是最有效的基础离子转运的调制器。急性治疗（5分钟）的Calu-3细胞与TDCA（25 μ M）的基底侧引起的刺激I-SC，和细胞外Cl-的去除废除这种反应。TDCA增加了囊性纤维化跨膜传导调节因子（CFTR）依赖性电流，而CFTR抑制剂CFTRinh 172预处理可消除该电流。TDCA处理还增加了通过钙激活氯离子（CaCC）通道的Cl-分泌，并增加了Na+/K+泵电流。用TDCA急性处理导致Calu-3细胞中Ca 2+的快速细胞内流和cAMP水平增加。INT-777的胆汁酸受体选择性激活显示TGR 5定位于基底外侧膜，作为参与TDCA诱导的Cl-分泌的受体。总之，我们第一次证明，低浓度的胆汁酸可以调节气道上皮细胞中的Cl分泌，并且这种效果取决于暴露于胆汁酸的持续时间和侧性。
Bile acids resulting from the aspiration of gastroesophageal refluxate are often present in the lower airways of people with cystic fibrosis and other respiratory distress diseases. Surprisingly, there is little or no information on the modulation of airway epithelial ion transport by bile acids. The secretory effect of a variety of conjugated and unconjugated secondary bile acids was investigated in Calu-3 airway epithelial cells grown under an air-liquid interface and mounted in Ussing chambers. Electrogenic transepithelial ion transport was measured as short-circuit current (I-sc). The taurine-conjugated secondary bile acid, taurodeoxycholic acid (TDCA), was found to be the most potent modulator of basal ion transport. Acute treatment (5 min) of Calu-3 cells with TDCA (25 mu M) on the basolateral side caused a stimulation of I-sc, and removal of extracellular Cl- abolished this response. TDCA produced an increase in the cystic fibrosis transmembrane conductance regulator (CFTR)-dependent current that was abolished by pretreatment with the CFTR inhibitor CFTRinh172. TDCA treatment also increased Cl- secretion through calcium-activated chloride (CaCC) channels and increased the Na+/K+ pump current. Acute treatment with TDCA resulted in a rapid cellular influx of Ca2+ and increased cAMP levels in Calu-3 cells. Bile acid receptor-selective activation with INT-777 revealed TGR5 localized at the basolateral membrane as the receptor involved in TDCA-induced Cl- secretion. In summary, we demonstrate for the first time that low concentrations of bile acids can modulate Cl secretion in airway epithelial cells, and this effect is dependent on both the duration and sidedness of exposure to the bile acid.