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PLoS One. 2012;7(8):e44059. doi: 10.1371/journal.pone.0044059. Epub 2012 Aug 24.

CFTR regulates early pathogenesis of chronic obstructive lung disease in βENaC-overexpressing mice.

Author information

  • 1Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research, University of Heidelberg, Heidelberg, Germany.

Abstract

BACKGROUND:

Factors determining the onset and severity of chronic obstructive pulmonary disease remain poorly understood. Previous studies demonstrated that airway surface dehydration in βENaC-overexpressing (βENaC-Tg) mice on a mixed genetic background caused either neonatal mortality or chronic obstructive lung disease suggesting that the onset of lung disease was modulated by the genetic background.

METHODS:

To test this hypothesis, we backcrossed βENaC-Tg mice onto two inbred strains (C57BL/6 and BALB/c) and studied effects of the genetic background on neonatal mortality, airway ion transport and airway morphology. Further, we crossed βENaC-Tg mice with CFTR-deficient mice to validate the role of CFTR in early lung disease.

RESULTS:

We demonstrate that the C57BL/6 background conferred increased CFTR-mediated Cl(-) secretion, which was associated with decreased mucus plugging and mortality in neonatal βENaC-Tg C57BL/6 compared to βENaC-Tg BALB/c mice. Conversely, genetic deletion of CFTR increased early mucus obstruction and mortality in βENaC-Tg mice.

CONCLUSIONS:

We conclude that a decrease or absence of CFTR function in airway epithelia aggravates the severity of early airway mucus obstruction and related mortality in βENaC-Tg mice. These results suggest that genetic or environmental factors that reduce CFTR activity may contribute to the onset and severity of chronic obstructive pulmonary disease and that CFTR may serve as a novel therapeutic target.

PMID:
22937152
[PubMed - indexed for MEDLINE]
PMCID:
PMC3427321
Free PMC Article
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