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Published ahead of print on October 10, 2008, doi:10.1164/rccm.200803-442OC

Am. J. Respir. Crit. Care Med., Volume 178, Number 12, December 2008, 1245-1256

A more recent version of this article appeared on December 15, 2008
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Submitted on March 21, 2008
Accepted on October 10, 2008

Preventive but not Late Amiloride Therapy Reduces Morbidity and Mortality of Lung Disease in {beta}ENaC-overexpressing Mice

Zhe Zhou1, Diana Treis1, Susanne C Schubert1, Maria Harm1, Jolanthe Schatterny1, Stephanie Hirtz1, Julia Duerr1, Richard C Boucher2, and Marcus A Mall1*

1 Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Heidelberg, Germany, 2 Cystic Fibrosis/Pulmonary Research and Treatment Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States

* To whom correspondence should be addressed. E-mail: marcus.mall{at}med.uni-heidelberg.de.

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 CF patients 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 {beta}ENaC-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 remodelling. 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 {beta}ENaC-overexpressing mice. In contrast, consistent with previous human trials in CF patients, amiloride administration did not have benefits if treatment was started after the development of CF-like lung disease in {beta}ENaC-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 prior to the onset of lung disease.
Key words: epithelial Na+ channels (ENaC) • airway surface liquid (ASL) • cystic fibrosis (CF) • pharmacotherapy • Mucus




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