Published ahead of print on December 13, 2007, doi:10.1164/rccm.200708-1233OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200708-1233OC
Development of Chronic Bronchitis and Emphysema in β-Epithelial Na+ Channel–Overexpressing Mice1 Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Heidelberg, Germany; 2 Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan; and 3 Cystic Fibrosis/Pulmonary Research and Treatment Center and 4 Division of Pulmonary and Critical Care Medicine, Department of Medicine, 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: Chronic obstructive pulmonary disease is a leading cause of death worldwide, but its pathogenesis is not well understood. Previous studies have shown that airway surface dehydration in β-epithelial Na+ channel (βENaC)–overexpressing mice caused a chronic lung disease with high neonatal pulmonary mortality and chronic bronchitis in adult survivors. Objectives: The aim of this study was to identify the initiating lesions and investigate the natural progression of lung disease caused by airway surface dehydration. Methods: Lung morphology, gene expression, bronchoalveolar lavage, and lung mechanics were studied at different ages in βENaC-overexpressing mice.
Measurements and Main Results: Mucus obstruction in βENaC-overexpressing mice originated in the trachea in the first days of life and was associated with hypoxia, airway epithelial necrosis, and death. In surviving βENaC-overexpressing mice, mucus obstruction extended into the lungs and was accompanied by goblet cell metaplasia, increased mucin expression, and airway inflammation with transient perinatal increases in tumor necrosis factor- Conclusions: Our studies demonstrate that airway surface dehydration is sufficient to initiate persistent neutrophilic airway inflammation with chronic airways mucus obstruction and to cause transient eosinophilic airway inflammation and emphysema. These results suggest that deficient airway surface hydration may play a critical role in the pathogenesis of chronic obstructive pulmonary diseases of different etiologies and serve as a target for novel therapies.
Key Words: chronic obstructive lung disease • epithelial Na+ channels • airway surface liquid • inflammation • mucus
This article has been cited by other articles:
|
.JPG?ad=19105&adview=true)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
and macrophages, IL-13 and eosinophils, and persistent increases in keratinocyte-derived cytokine (KC), neutrophils, and chitinases in the lung. βENaC-overexpressing mice also developed emphysema with increased lung volumes, distal airspace enlargement, and increased lung compliance. 
