Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice

doi:doi:10.1038/nm1028

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in defective epithelial cAMP-dependent Cl^- secretion and increased airway Na⁺ absorption. The mechanistic links between these altered ion transport processes and the pathogenesis of cystic fibrosis lung disease, however, are unclear. To test the hypothesis that accelerated Na⁺ transport alone can produce cystic fibrosis-like lung disease, we generated mice with airway-specific overexpression of epithelial Na⁺ channels (ENaC). Here we show that increased airway Na⁺ absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces. Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance. We conclude that increasing airway Na⁺ absorption initiates cystic fibrosis-like lung disease and produces a model for the study of the pathogenesis and therapy of this disease.

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