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Am J Respir Crit Care Med. 2008 Apr 1;177(7):730-42. Epub 2007 Dec 13.

Development of chronic bronchitis and emphysema in beta-epithelial Na+ channel-overexpressing mice.

Author information

  • 1Pediatric Pulmonology and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany. marcus.mall@med.uni-heidelberg.de

Abstract

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 beta-epithelial Na(+) channel (betaENaC)-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 betaENaC-overexpressing mice.

MEASUREMENTS AND MAIN RESULTS:

Mucus obstruction in betaENaC-overexpressing mice originated in the trachea in the first days of life and was associated with hypoxia, airway epithelial necrosis, and death. In surviving betaENaC-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-alpha and macrophages, IL-13 and eosinophils, and persistent increases in keratinocyte-derived cytokine (KC), neutrophils, and chitinases in the lung. betaENaC-overexpressing mice also developed emphysema with increased lung volumes, distal airspace enlargement, and increased lung compliance.

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.

PMID:
18079494
PMCID:
PMC2277210
DOI:
10.1164/rccm.200708-1233OC
[PubMed - indexed for MEDLINE]
Free PMC Article
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