{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T03:50:52Z","timestamp":1790481052343,"version":"4.1.0"},"reference-count":46,"publisher":"American Physiological Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2013,4,1]]},"abstract":"<jats:p> Airway surface hydration depends on the balance between transepithelial Na<jats:sup>+<\/jats:sup> absorption and Cl<jats:sup>\u2212<\/jats:sup> 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<jats:sup>+<\/jats:sup> channel \u03b2 subunit in transgenic mice (\u03b2ENaC-Tg) produces unregulated Na<jats:sup>+<\/jats:sup> hyperabsorption and results in CF-like airway surface dehydration, mucus obstruction, inflammation, and increased neonatal mortality. To investigate whether the combination of airway Na<jats:sup>+<\/jats:sup> hyperabsorption and absent Cftr-mediated Cl<jats:sup>\u2212<\/jats:sup> secretion resulted in more severe lung pathology, we generated double-mutant \u0394F508 CF\/\u03b2ENaC-Tg mice. Survival of \u0394F508 CF\/\u03b2ENaC-Tg mice was reduced compared with \u03b2ENaC-Tg or \u0394F508 CF mice. Absence of functional Cftr did not affect endogenous or transgenic ENaC currents but produced reduced basal components of Cl<jats:sup>\u2212<\/jats:sup> secretion and tracheal cartilaginous defects in both \u0394F508 CF and \u0394F508 CF\/\u03b2ENaC-Tg mice. Neonatal \u0394F508 CF\/\u03b2ENaC-Tg mice exhibited higher neutrophilic pulmonary inflammation and club cell (Clara cell) necrosis compared with \u03b2ENaC-Tg littermates. Neonatal \u0394F508 CF\/\u03b2ENaC-Tg mice also exhibited spontaneous bacterial infections, but the bacterial burden was similar to that of \u03b2ENaC-Tg littermates. Adult \u0394F508 CF\/\u03b2ENaC-Tg mice exhibited pathological changes associated with eosinophilic crystalline pneumonia, a phenotype not observed in age-matched \u03b2ENaC-Tg mice. Collectively, these data suggest that the combined abnormalities in Na<jats:sup>+<\/jats:sup> absorption and Cl<jats:sup>\u2212<\/jats:sup> 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 \u03b2ENaC overexpression and absent CFTR-mediated Cl<jats:sup>\u2212<\/jats:sup> secretion to produce the increased neonatal mortality observed in \u0394F508 CF\/\u03b2ENaC-Tg mice. <\/jats:p>","DOI":"10.1152\/ajplung.00150.2012","type":"journal-article","created":{"date-parts":[[2013,4,1]],"date-time":"2013-04-01T16:20:48Z","timestamp":1364833248000},"page":"L469-L480","source":"Crossref","is-referenced-by-count":40,"title":["Loss of <i>Cftr<\/i> function exacerbates the phenotype of Na<sup>+<\/sup> hyperabsorption in murine airways"],"prefix":"10.1152","volume":"304","author":[{"given":"Alessandra","family":"Livraghi-Butrico","sequence":"first","affiliation":[{"name":"Cystic Fibrosis\/Pulmonary Research and Treatment Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 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