Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator-dependent anion and fluid secretion in airway epithelia.
J Physiol
; 594(6): 1643-61, 2016 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-26574187
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Bicarbonatos
/
Dióxido de Carbono
/
Cloretos
/
AMP Cíclico
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Regulador de Condutância Transmembrana em Fibrose Cística
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Mucosa Respiratória
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Hipercapnia
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article