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Pharmacology - Physiology - Respiratory Medicine

CFTR Regulates Early Pathogenesis of Chronic Obstructive Lung Disease in ßENaC-Overexpressing Mice
Published: Friday, August 24, 2012
Author: Bjarki Johannesson et al.

by Bjarki Johannesson, Stephanie Hirtz, Jolanthe Schatterny, Carsten Schultz, Marcus A. Mall


Factors determining the onset and severity of chronic obstructive pulmonary disease remain poorly understood. Previous studies demonstrated that airway surface dehydration in ßENaC-overexpressing (ßENaC-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.


To test this hypothesis, we backcrossed ßENaC-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 ßENaC-Tg mice with CFTR-deficient mice to validate the role of CFTR in early lung disease.


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


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 ßENaC-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.