| First Author | Livraghi-Butrico A | Year | 2013 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 304 |
| Issue | 7 | Pages | L469-80 |
| PubMed ID | 23377346 | Mgi Jnum | J:195159 |
| Mgi Id | MGI:5476597 | Doi | 10.1152/ajplung.00150.2012 |
| Citation | Livraghi-Butrico A, et al. (2013) Loss of Cftr function exacerbates the phenotype of Na+ hyperabsorption in murine airways. Am J Physiol Lung Cell Mol Physiol 304(7):L469-80 |
| abstractText | 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 (betaENaC-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 DeltaF508 CF/betaENaC-Tg mice. Survival of DeltaF508 CF/betaENaC-Tg mice was reduced compared with betaENaC-Tg or DeltaF508 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 DeltaF508 CF and DeltaF508 CF/betaENaC-Tg mice. Neonatal DeltaF508 CF/betaENaC-Tg mice exhibited higher neutrophilic pulmonary inflammation and club cell (Clara cell) necrosis compared with betaENaC-Tg littermates. Neonatal DeltaF508 CF/betaENaC-Tg mice also exhibited spontaneous bacterial infections, but the bacterial burden was similar to that of betaENaC-Tg littermates. Adult DeltaF508 CF/betaENaC-Tg mice exhibited pathological changes associated with eosinophilic crystalline pneumonia, a phenotype not observed in age-matched betaENaC-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 betaENaC overexpression and absent CFTR-mediated Cl(-) secretion to produce the increased neonatal mortality observed in DeltaF508 CF/betaENaC-Tg mice. |
