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

ABSTRACT:

Background

Factors determining the onset and severity of chronic obstructive pulmonary disease remain poorly understood. Previous studies demonstrated that airway surface dehydration in ?ENaC-overexpressing (?ENaC-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 ?ENaC-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 ?ENaC-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 ?ENaC-Tg C57BL/6 compared to ?ENaC-Tg BALB/c mice. Conversely, genetic deletion of CFTR increased early mucus obstruction and mortality in ?ENaC-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 ?ENaC-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.

SUBMITTER: Johannesson B 

PROVIDER: S-EPMC3427321 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature