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

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.

• Authors: Marcus A Mall, Jack R Harkema, Joanna B Trojanek, Diana Treis, Alessandra Livraghi, Susanne Schubert, Zhe Zhou, Silvia M Kreda, Stephen L Tilley, Elizabeth J Hudson, Wanda K O'Neal, Richard C Boucher
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 177 Issue 7 Pg. 730-42 (Apr 01 2008) ISSN: 1535-4970 [Electronic] United States
• PMID: 18079494 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Epithelial Sodium Channels

Topics

• Animals
• Animals, Newborn
• Bronchitis, Chronic (physiopathology)
• Dehydration
• Disease Progression
• Epithelial Sodium Channels (metabolism)
• Gene Expression
• Inflammation
• Longitudinal Studies
• Mice
• Mice, Inbred Strains
• Mucociliary Clearance
• Pulmonary Disease, Chronic Obstructive (physiopathology)
• Pulmonary Emphysema (physiopathology)
• Respiratory Mucosa (metabolism)