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


OBJECTIVE
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.


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.
Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Heidelberg, Germany.
Zhe
Z
Zhou
Diana
D
Treis
Susanne C
SC
Schubert
Maria
M
Harm
Jolanthe
J
Schatterny
Stephanie
S
Hirtz
Julia
J
Duerr
Richard C
RC
Boucher
Marcus A
MA
Mall
D000584:Amiloride / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D003550:Cystic Fibrosis / Q000453:epidemiology / Q000378:metabolism / Q000517:prevention & control; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D053503:Epithelial Sodium Channels / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D018793:Interleukin-13 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000453:epidemiology / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D009017:Morbidity / Q000639:trends; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome
D053503:Epithelial Sodium Channels; D018793:Interleukin-13; D026941:Sodium Channel Blockers; D000584:Amiloride; D004247:DNA; D012964:Sodium; D011188:Potassium