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Molecular basis for pH-dependent mucosal dehydration in cystic fibrosis airways

2013; National Academy of Sciences; Volume: 110; Issue: 40 Linguagem: Inglês

10.1073/pnas.1311999110

1091-6490

Alaina L. Garland, William G. Walton, Raymond D. Coakley, Chong Da Tan, Rodney C. Gilmore, Carey Hobbs, Ashutosh Tripathy, Lucy A Clunes, Sompop Bencharit, M. Jackson Stutts, Laurie Betts, Matthew R. Redinbo, Robert Tarran,

Ion Transport and Channel Regulation

Significance Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene, which codes for a chloride/bicarbonate channel whose absence leads to dehydration and acidification of CF airways. A contributing factor to CF lung disease is dysregulation of the epithelial Na + channel (ENaC), which exacerbates mucus dehydration. Here, we show that ENaC hyperactivity in CF airways is direct consequence of acidic airway surface liquid (ASL) and that ASL hydration is restored by raising ASL pH. Additionally, we show that short palate lung and nasal epithelial clone 1, the most abundant gene in airway epithelia, is the extracellular pH-sensitive factor that inhibits ENaC in normal but not CF airways. We suggest that future CF therapy be directed toward raising the pH of CF airways.