Loss of Cftr function exacerbates the phenotype of Na+ hyperabsorption in murine airways

Livraghi-Butrico A, Kelly EJ, Wilkinson KJ, Rogers TD, Gilmore RC, Harkema JR, Randell SH, Boucher RC, O'Neal WK, Grubb BR. Loss of Cftr function exacerbates the phenotype of Na+ hyperabsorption in murine airways. Am J Physiol Lung Cell Mol Physiol 304: L469-L480, 2013. First published February 1, 2013; doi:10.1152/ajplung.00150.2012.-Airway surface hydration depends on the balance between transepithelial Na+ absorption and Cl- secretion. In adult mice, absence of functional cystic fibrosis transmembrane conductance regulator (Cftr) fails to recapitulate human cystic fibrosis (CF) lung disease. In contrast, overexpression of the epithelial Na+ channel beta subunit in transgenic mice (beta ENaC-Tg) produces unregulated Na+ hyperabsorption and results in CF-like airway surface dehydration, mucus obstruction, inflammation, and increased neonatal mortality. To investigate whether the combination of airway Na+ hyperabsorption and absent Cftr-mediated Cl- secretion resulted in more severe lung pathology, we generated double-mutant Delta F508 CF/beta ENaC-Tg mice. Survival of Delta F508 CF/beta ENaC-Tg mice was reduced compared with beta ENaC-Tg or Delta F508 CF mice. Absence of functional Cftr did not affect endogenous or transgenic ENaC currents but produced reduced basal components of Cl- secretion and tracheal cartilaginous defects in both Delta F508 CF and Delta F508 CF/beta ENaC-Tg mice. Neonatal Delta F508 CF/beta ENaC-Tg mice exhibited higher neutrophilic pulmonary inflammation and club cell (Clara cell) necrosis compared with beta ENaC-Tg littermates. Neonatal Delta F508 CF/beta ENaC-Tg mice also exhibited spontaneous bacterial infections, but the bacterial burden was similar to that of beta ENaC-Tg littermates. Adult Delta F508 CF/beta ENaC-Tg mice exhibited pathological changes associated with eosinophilic crystalline pneumonia, a phenotype not observed in age-matched beta ENaC-Tg mice. Collectively, these data suggest that the combined abnormalities in Na+ absorption and Cl- secretion produce more severe lung disease than either defect alone. Airway cartilage abnormalities, airway cell necrosis, and exaggerated neutrophil infiltration likely interact with defective mucus clearance caused by beta ENaC overexpression and absent CFTR-mediated Cl- secretion to produce the increased neonatal mortality observed in Delta F508 CF/beta ENaC-Tg mice.