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Preventive but Not Late Amiloride Therapy Reduces Morbidity and Mortality of Lung Disease in βENaC-overexpressing Mice

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

Correspondence and requests for reprints should be addressed to Marcus A. Mall, M.D., Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany. 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 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 βENaC-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 βENaC-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 βENaC-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.

Key Words: epithelial Na⁺ channels • airway surface liquid • cystic fibrosis • pharmacotherapy • mucus

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Increased airway Na+ absorption produces airway surface dehydration and deficient mucociliary clearance, and plays an important role in the pathogenesis of cystic fibrosis (CF) lung disease. What This Study Adds to the Field This study demonstrates that early, but not late, inhibition of increased airway Na+ absorption provides an effective therapy for CF-like lung disease in a murine disease model. This preventive paradigm may potentially be of benefit for the treatment of patients with CF.

 

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Amiloride: Still a Viable Treatment Option in Cystic Fibrosis?

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AJRCCM 2008 178: 1191-1192. [Full Text]  

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				F. Ratjen and A. Bush Amiloride: Still a Viable Treatment Option in Cystic Fibrosis? Am. J. Respir. Crit. Care Med., December 15, 2008; 178(12): 1191 - 1192. [Full Text] [PDF]