title: Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator-dependent anion and fluid secretion in airway epithelia.
abstract: Hypercapnia is clinically defined as an arterial blood partial pressure of CO2 of above 40 mmHg and is a feature of chronic lung disease. In previous studies we have demonstrated that hypercapnia modulates agonist-stimulated cAMP levels through effects on transmembrane adenylyl cyclase activity. In the airways, cAMP is known to regulate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated anion and fluid secretion, which contributes to airway surface liquid homeostasis. The aim of the current work was to investigate if hypercapnia could modulate cAMP-regulated ion and fluid transport in human airway epithelial cells. We found that acute exposure to hypercapnia significantly reduced forskolin-stimulated elevations in intracellular cAMP as well as both adenosine- and forskolin-stimulated increases in CFTR-dependent transepithelial short-circuit current, in polarised cultures of Calu-3 human airway cells. This CO2 -induced reduction in anion secretion was not due to a decrease in HCO3 (-) transport given that neither a change in CFTR-dependent HCO3 (-) efflux nor Na(+) /HCO3 (-) cotransporter-dependent HCO3 (-) influx were CO2 -sensitive. Hypercapnia also reduced the volume of forskolin-stimulated fluid secretion over 24 h, yet had no effect on the HCO3 (-) content of the secreted fluid. Our data reveal that hypercapnia reduces CFTR-dependent, electrogenic Cl(-) and fluid secretion, but not CFTR-dependent HCO3 (-) secretion, which highlights a differential sensitivity of Cl(-) and HCO3 (-) transporters to raised CO2 in Calu-3 cells. Hypercapnia also reduced forskolin-stimulated CFTR-dependent anion secretion in primary human airway epithelia. Based on current models of airways biology, a reduction in fluid secretion, associated with hypercapnia, would be predicted to have important consequences for airways hydration and the innate defence mechanisms of the lungs.
authors.affiliation: Institute for Cell & Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.|Department of Physiology, McIntyre Medical Sciences Building, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 1Y6.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Turner
authors.affiliation: Institute for Cell & Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Vinciane
authors.initials: V
authors.lastname: Saint-Criq
authors.affiliation: Institute for Cell & Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Waseema
authors.initials: W
authors.lastname: Patel
authors.affiliation: Institute for Cell & Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Salam H
authors.initials: SH
authors.lastname: Ibrahim
authors.affiliation: Institute for Cell & Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Verdon
authors.affiliation: Institute for Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ward
authors.affiliation: Institute for Cell & Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: James P
authors.initials: JP
authors.lastname: Garnett
authors.affiliation: Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, 27599, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tarran
authors.affiliation: School of Biological and Biomedical Sciences, Durham University, South Road, Durham, DH1 3LE, UK.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Cann
authors.affiliation: Institute for Cell & Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gray
mesh_terms: D001639:Bicarbonates / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D006801:Humans; D006935:Hypercapnia / Q000378:metabolism*; D017136:Ion Transport; D020545:Respiratory Mucosa / Q000378:metabolism*; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism
chemical_list: D001639:Bicarbonates; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002245:Carbon Dioxide; D012964:Sodium; D000242:Cyclic AMP