• Marcus A Mall.
• Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Germany. marcus.mall@med.uni-heidelberg.de
• Exp. Physiol. 2009 Feb 1; 94 (2): 171-4.

AbstractIncreased airway Na(+) absorption mediated by the amiloride-sensitive epithelial Na(+) channel (ENaC) is a basic defect in cystic fibrosis (CF) lung disease. Cystic fibrosis is one of the most common lethal hereditary diseases and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR acts as a cAMP-dependent Cl(-) channel and regulator of ENaC, and CFTR dysfunction causes impaired Cl(-) secretion and increased Na(+) absorption in the airways of CF patients. Evidence from in vitro studies suggested that increased Na(+) absorption produces airway surface liquid (ASL) volume depletion and led to the generation of transgenic mice with airway-specific overexpression of ENaC to elucidate the role of this mechanism in the in vivo pathogenesis of lung disease. Studies of the pulmonary phenotype of betaENaC-overexpressing mice demonstrated that increased airway Na(+) absorption caused ASL depletion and reduced mucus transport, producing a CF-like lung disease with airway mucus plugging, chronic airway inflammation and pulmonary mortality. Further, recent pharmacological studies demonstrated that preventive, but not late, inhibition of increased airway Na(+) absorption with the ENaC blocker amiloride reduced morbidity and mortality in this murine model of CF lung disease. These results support a critical role of ENaC in the in vivo pathogenesis of CF lung disease and suggest that amiloride may be an effective preventive therapy for CF patients.

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