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

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• 作者：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
• 刊名：The Journal of Physiology
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：594
• 期：6
• 页码：1643-1661
• 全文大小：976.8KB
• ISSN：1469-7793

文摘

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.