This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200708-1233OCv1 177/7/730    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mall, M. A. Articles by Boucher, R. C. Search for Related Content PubMed PubMed Citation Articles by Mall, M. A. Articles by Boucher, R. C.

Development of Chronic Bronchitis and Emphysema in β-Epithelial Na⁺ Channel–Overexpressing Mice

¹ 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- 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.

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

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Airway surface dehydration is a key feature of cystic fibrosis and produces chronic bronchitis in mice. The initiating lesions and the natural history of lung disease caused by airway surface dehydration have not been elucidated. What This Study Adds to the Field 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.

 

This article has been cited by other articles:

				L. Knudsen, E. R. Weibel, H. J. G. Gundersen, F. V. Weinstein, and M. Ochs Assessment of air space size characteristics by intercept (chord) measurement: an accurate and efficient stereological approach J Appl Physiol, February 1, 2010; 108(2): 412 - 421. [Abstract] [Full Text] [PDF]

				M. Yee, P. R. Chess, S. A. McGrath-Morrow, Z. Wang, R. Gelein, R. Zhou, D. A. Dean, R. H. Notter, and M. A. O'Reilly Neonatal oxygen adversely affects lung function in adult mice without altering surfactant composition or activity Am J Physiol Lung Cell Mol Physiol, October 1, 2009; 297(4): L641 - L649. [Abstract] [Full Text] [PDF]

				B. Lubamba, J. Lebacq, P. Lebecque, R. Vanbever, A. Leonard, P. Wallemacq, and T. Leal Airway Delivery of Low-Dose Miglustat Normalizes Nasal Potential Difference in F508del Cystic Fibrosis Mice Am. J. Respir. Crit. Care Med., June 1, 2009; 179(11): 1022 - 1028. [Abstract] [Full Text] [PDF]

				A. Livraghi, B. R. Grubb, E. J. Hudson, K. J. Wilkinson, J. K. Sheehan, M. A. Mall, W. K. O'Neal, R. C. Boucher, and S. H. Randell Airway and Lung Pathology Due to Mucosal Surface Dehydration in {beta}-Epithelial Na+ Channel-Overexpressing Mice: Role of TNF-{alpha} and IL-4R{alpha} Signaling, Influence of Neonatal Development, and Limited Efficacy of Glucocorticoid Treatment J. Immunol., April 1, 2009; 182(7): 4357 - 4367. [Abstract] [Full Text] [PDF]

				F. Ratjen Update in Cystic Fibrosis 2008 Am. J. Respir. Crit. Care Med., March 15, 2009; 179(6): 445 - 448. [Full Text] [PDF]

				M. A. Mall Role of the amiloride-sensitive epithelial Na+ channel in the pathogenesis and as a therapeutic target for cystic fibrosis lung disease Exp Physiol, February 1, 2009; 94(2): 171 - 174. [Abstract] [Full Text] [PDF]

				F. Ratjen and A. Bush Amiloride: Still a Viable Treatment Option in Cystic Fibrosis? Am. J. Respir. Crit. Care Med., December 15, 2008; 178(12): 1191 - 1192. [Full Text] [PDF]

				Z. Zhou, D. Treis, S. C. Schubert, M. Harm, J. Schatterny, S. Hirtz, J. Duerr, R. C. Boucher, and M. A. Mall Preventive but Not Late Amiloride Therapy Reduces Morbidity and Mortality of Lung Disease in {beta}ENaC-overexpressing Mice Am. J. Respir. Crit. Care Med., December 15, 2008; 178(12): 1245 - 1256. [Abstract] [Full Text] [PDF]

				K. F. Chung and I. M. Adcock Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction Eur. Respir. J., June 1, 2008; 31(6): 1334 - 1356. [Abstract] [Full Text] [PDF]