Preventive but not late amiloride therapy reduces morbidity and mortality of lung disease in betaENaC-overexpressing mice.
Am J Respir Crit Care Med
; 178(12): 1245-56, 2008 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-18849497
ABSTRACT
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 MAINRESULTS:
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.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
DNA
/
Regulação da Expressão Gênica
/
Bloqueadores dos Canais de Sódio
/
Canais Epiteliais de Sódio
/
Amilorida
/
Pneumopatias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Am J Respir Crit Care Med
Assunto da revista:
TERAPIA INTENSIVA
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Alemanha