CFTR Regulates Early Pathogenesis of Chronic Obstructive Lung Disease in βENaC-Overexpressing Mice

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