title: Development of chronic bronchitis and emphysema in beta-epithelial Na+ channel-overexpressing mice.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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: Pediatric 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
authors: Marcus A
authors: MA
authors: Mall
authors: Jack R
authors: JR
authors: Harkema
authors: Joanna B
authors: JB
authors: Trojanek
authors: Diana
authors: D
authors: Treis
authors: Alessandra
authors: A
authors: Livraghi
authors: Susanne
authors: S
authors: Schubert
authors: Zhe
authors: Z
authors: Zhou
authors: Silvia M
authors: SM
authors: Kreda
authors: Stephen L
authors: SL
authors: Tilley
authors: Elizabeth J
authors: EJ
authors: Hudson
authors: Wanda K
authors: WK
authors: O'Neal
authors: Richard C
authors: RC
authors: Boucher
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D029481:Bronchitis, Chronic / Q000503:physiopathology; D003681:Dehydration; D018450:Disease Progression; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D015870:Gene Expression; D007249:Inflammation; D008137:Longitudinal Studies; D051379:Mice; D008815:Mice, Inbred Strains; D009079:Mucociliary Clearance; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D011656:Pulmonary Emphysema / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000378:metabolism*
chemical_list: D053503:Epithelial Sodium Channels