Departments of Molecular Medicine and.
Respiratory Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
Am J Physiol Lung Cell Mol Physiol. 2014 Sep 1;307(5):L407-18. doi: 10.1152/ajplung.00352.2013. Epub 2014 Jul 3.
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 (Isc). 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 μM) on the basolateral side caused a stimulation of Isc, 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 Ca(2+) 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.
胆酸是胃食管反流物被吸入后产生的，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，关于胆酸对气道上皮离子转运的调节作用，目前的信息很少或几乎没有。本研究在气液界面下培养的 Calu-3 气道上皮细胞中以及在 Ussing 室中安装的细胞中，研究了各种结合型和非结合型次级胆酸对气道上皮离子转运的分泌作用。电致性跨上皮离子转运以短路电流（Isc）来测量。发现牛磺胆酸（TDCA）是基础离子转运的最有效调节剂。TDCA（25 μM）在基底外侧急性处理（5 min）Calu-3 细胞可刺激 Isc，并且去除细胞外 Cl(-) 可消除该反应。TDCA 增加了囊性纤维化跨膜电导调节剂（CFTR）依赖性电流，CFTR 抑制剂 CFTRinh172 的预处理可消除该反应。TDCA 处理还通过钙激活氯离子（CaCC）通道增加 Cl(-) 分泌，并增加 Na(+)/K(+) 泵电流。TDCA 急性处理可导致 Calu-3 细胞内 Ca(2+)的快速内流和 cAMP 水平的增加。INT-777 对胆酸受体的选择性激活表明，TGR5 定位于基底外侧膜，是 TDCA 诱导的 Cl(-)分泌所涉及的受体。总之，我们首次证明低浓度胆酸可调节气道上皮细胞中的 Cl(-)分泌，这种作用依赖于暴露于胆酸的持续时间和侧位。
