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

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 ßENaC-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.

Preventive but not late amiloride therapy reduces morbidity and mortality of lung disease in betaENaC-overexpressing mice.

RATIONALE: Increased airway Na(+) absorption mediated by epithelial Na(+) channels (ENaC) is a characteristic abnormality in the pathogenesis of cystic fibrosis (CF) lung disease. However, inhalation therapy with the ENaC blocker amiloride did not have therapeutic benefits in patients with CF with established lung disease. OBJECTIVES: We hypothesized that preventive inhibition of increased Na(+) absorption in a structurally normal lung may be required for effective therapy of CF lung disease in vivo, and that therapeutic effects of late amiloride intervention may be impeded by the chronic disease process. METHODS: To test this hypothesis in vivo, we used the betaENaC-overexpression mouse as a model of CF lung disease and determined therapeutic effects of preventive versus late amiloride therapy on survival, airway mucus plugging, chronic bronchitis, and airway remodeling. MEASUREMENTS AND MAIN RESULTS: We show that early intervention, i.e., from the first day of life, with the intranasal administration of amiloride significantly reduced pulmonary mortality, airway mucus obstruction, epithelial necrosis, goblet cell metaplasia, and airway inflammation in betaENaC-overexpressing mice. In contrast, consistent with previous human trials in patients with CF, amiloride administration did not have benefits if treatment was started after the development of CF-like lung disease in betaENaC-overexpressing mice. CONCLUSIONS: We conclude that preventive inhibition of increased airway Na(+) absorption provides an effective therapy for CF-like lung disease in vivo. These results suggest that amiloride therapy may be an effective preventive therapy for patients with CF if initiated early in life before the onset of lung disease.