Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator-dependent anion and fluid secretion in airway epithelia.
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| 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.
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| Authors | Mark J Turner, Vinciane Saint-Criq, Waseema Patel, Salam H Ibrahim, Bernard Verdon, Christopher Ward, James P Garnett, Robert Tarran, Martin J Cann, Michael A Gray |
| Journal | The Journal of physiology (J Physiol) Vol. 594 Issue 6 Pg. 1643-61 (Mar 15 2016) ISSN: 1469-7793 [Electronic] England |
| PMID | 26574187 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2015 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. |
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