The ENaC-overexpressing mouse as a model of cystic fibrosis lung disease

Abstract

Chronic lung disease remains the major cause of morbidity and mortality of cystic fibrosis (CF) patients. Cftr mutant mice developed severe intestinal obstruction, but did not exhibit the characteristic CF ion transport defects (i.e. deficient cAMP-dependent Cl(-) secretion and increased Na(+) absorption) in the lower airways, and failed to develop CF-like lung disease. These observations led to the generation of transgenic mice with airway-specific overexpression of the epithelial Na(+) channel (ENaC) as an alternative approach to mimic CF ion transport pathophysiology in the lung. Studies of the phenotype of βENaC-transgenic mice demonstrated that increased airway Na(+) absorption causes airway surface liquid (ASL) depletion, reduced mucus transport and a spontaneous CF-like lung disease with airway mucus obstruction and chronic airway inflammation. Here, we summarize approaches that can be applied for studies of the complex in vivo pathogenesis and preclinical evaluation of novel therapeutic strategies in this model of CF lung disease.

New Insights into the Epithelial Sodium Channel Using Directed Mutagenesis

“…More recently, several studies pointed to ENaC as a potential target for cystic fibrosis (Zhou et al, 2011), a pathology characterized by an impaired Cl -secretion through the cystic fibrosis transmembrane conductance regulator (CFTR) and an increase of Na + reabsorption through ENaC. The studies of mutations involved in these diseases have been extremely helpful in determining the molecular mechanisms by which they lead to a dysfunction of ENaC.…”

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

“…31 Subsequent studies with these bENaC-Tg mice, demonstrated that increased ENaCmediated sodium absorption causes ASL depletion, hyperconcentrated mucus and impaired mucus clearance, and that these defects trigger CF-like lung disease with airway mucus plugging, spontaneous infection and inflammation, and structural lung damage in vivo. 30 The lung phenotype exhibited by the b-ENaC ovexpressing mouse was in fact more prominent that the one exhibited by CF-knockout mice that in general fail to recapitulate this characteristic manifestation of CF.…”

“…30). To mimic increased ENaC activity observed in CF airways and prevent unrelated pathologies in other organs, the Clara cell secretory protein (CCSP) promoter element was used to target expression of ENaC to mouse airways.…”

Pseudomonas aeruginosa Biofilm Formation in the CF Lung and Its Implications for Therapy

“…Mice with various CFTR alleles and/or overexpression of βENaC have been tested as infection models, but P. aeruginosa is generally cleared from the lungs of these animals (Grubb and Boucher 1999;Mall, Grubb et al 2004;Wilke, BuijsOfferman et al 2011;Zhou, Duerr et al 2011). Mice and humans have very different lung physiologies, which most likely account for the inability to establish chronic infection in "CF" mice (Wilke, Buijs-Offerman et al 2011).…”