Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice.
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.
Mall
Marcus
M
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. mmall@med.unc.edu
Grubb
Barbara R
BR
Harkema
Jack R
JR
O'Neal
Wanda K
WK
Boucher
Richard C
RC
D000818:Animals; D003550:Cystic Fibrosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009093:Mucus / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*
C505032:CFTR protein, human; D053503:Epithelial Sodium Channels; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012964:Sodium