title: Bile acids stimulate chloride secretion through CFTR and calcium-activated Cl- channels in Calu-3 airway epithelial cells.
abstract: 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.
authors.affiliation: Departments of Molecular Medicine and.
authors.forename: Siobhán M
authors.initials: SM
authors.lastname: Hendrick
authors.affiliation: Departments of Molecular Medicine and.
authors.forename: Magdalena S
authors.initials: MS
authors.lastname: Mroz
authors.affiliation: Respiratory Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Greene
authors.affiliation: Departments of Molecular Medicine and.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Keely
authors.affiliation: Departments of Molecular Medicine and bjpharvey@rcsi.ie.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Harvey
mesh_terms: D001647:Bile Acids and Salts / Q000494:pharmacology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012137:Respiratory System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001647:Bile Acids and Salts; C505032:CFTR protein, human; D018118:Chloride Channels; D002712:Chlorides; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002118:Calcium
keywords: airway epithelium; bile acid; secretion