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

Abstract

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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Figure 1: Expression of Scnn1b transgene and Na+ transport in airway epithelia of Scnn1b-transgenic mice.
Figure 2: Effects of βENaC overexpression on ASL volume and mucus transport.
Figure 3: Pulmonary mortality in Scnn1b-transgenic mice.
Figure 4: Pulmonary disease phenotype in surviving Scnn1b-transgenic mice.
Figure 5: Neutrophilic inflammation and slowed bacterial clearance in lungs of Scnn1b-transgenic mice.

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Acknowledgements

We thank E. Andrews, B. Brighton, K. Burns, M. Chua, B. Chun, S. Dix, R. Davis, T. Elred, E. Hudson, S. Randell, T. Rogers and C. Sun for expert technical assistance; T.R. Kleyman for mouse Scnn1a, Scnn1b and Scnn1c cDNAs; R. Thresher for transgenic vector pTG1; A.L. Smith for H. influenzae R3001 and R.K. Ernst for P. aeruginosa PA 10015 clinical isolates; I. Gilmour and U. Schwab for useful discussion; and B.H. Koller and M. J. Stutts for critical reading of the manuscript. This work was supported by grants from the National Institutes of Health (to R.C.B.), the Cystic Fibrosis Foundation (to M.M., W.K.O. and R.C.B.) and the Deutsche Forschungsgemeinschaft (DFG MA 2081/2–1 to M.M.).

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Correspondence to Marcus Mall or Richard C Boucher.

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R.C.B., B.R.G., W.K.O. and M.M. are listed on a patent filed by the University of North Carolina at Chapel Hill, describing this mouse model.

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Mall, M., Grubb, B., Harkema, J. et al. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat Med 10, 487–493 (2004). https://doi.org/10.1038/nm1028

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