Marcus Mall1, Barbara R Grubb1, Jack R Harkema2, Wanda K O'Neal1
& Richard C Boucher1
1
Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, The University of North Carolina at Chapel Hill, 7011 Thurston Bowles Building, Chapel Hill, North Carolina 27599-7248, USA.
2
Department of Pathobiology and Diagnostic Investigation, Michigan State University, 212 Food Safety and Toxicology Building, East Lansing, Michigan 48824, USA.
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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