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Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator-dependent anion and fluid secretion in airway epithelia.

Turner, M.J. and Saint-Crib, V. and Patel, W. and Ibrahim, S.H. and Verdon, B. and Ward, C. and Garnett, J.P. and Tarran, R. and Cann, M.J. and Gray, M.A. (2016) 'Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator-dependent anion and fluid secretion in airway epithelia.', Journal of physiology., 594 (6). pp. 1643-1661.


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.

Item Type:Article
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Publisher statement:© 2015 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Date accepted:05 November 2015
Date deposited:23 November 2015
Date of first online publication:20 December 2015
Date first made open access:20 December 2016

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