CFTR Regulates Early Pathogenesis of Chronic Obstructive Lung Disease in βENaC-Overexpressing Mice

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Abstract

Background

Factors determining the onset and severity of chronic obstructive pulmonary disease remain poorly understood. Previous studies demonstrated that airway surface dehydration in βENaC-overexpressing (βENaC-Tg) mice on a mixed genetic background caused either neonatal mortality or chronic obstructive lung disease suggesting that the onset of lung disease was modulated by the genetic background.

Methods

To test this hypothesis, we backcrossed βENaC-Tg mice onto two inbred strains (C57BL/6 and BALB/c) and studied effects of the genetic background on neonatal mortality, airway ion transport and airway morphology. Further, we crossed βENaC-Tg mice with CFTR-deficient mice to validate the role of CFTR in early lung disease.

Results

We demonstrate that the C57BL/6 background conferred increased CFTR-mediated Cl ⁻ secretion, which was associated with decreased mucus plugging and mortality in neonatal βENaC-Tg C57BL/6 compared to βENaC-Tg BALB/c mice. Conversely, genetic deletion of CFTR increased early mucus obstruction and mortality in βENaC-Tg mice.

Conclusions

We conclude that a decrease or absence of CFTR function in airway epithelia aggravates the severity of early airway mucus obstruction and related mortality in βENaC-Tg mice. These results suggest that genetic or environmental factors that reduce CFTR activity may contribute to the onset and severity of chronic obstructive pulmonary disease and that CFTR may serve as a novel therapeutic target.

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Most cited references 37

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The pathology of chronic obstructive pulmonary disease.

James C Hogg, Wim Timens (2009)

The pathogenesis of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune response to the inhalation of toxic particles and gases. Although tobacco smoking is the primary cause of this inhalation injury, many other environmental and occupational exposures contribute to the pathology of COPD. The immune inflammatory changes associated with COPD are linked to a tissue-repair and -remodeling process that increases mucus production and causes emphysematous destruction of the gas-exchanging surface of the lung. The common form of emphysema observed in smokers begins in the respiratory bronchioles near the thickened and narrowed small bronchioles that become the major site of obstruction in COPD. The mechanism(s) that allow small airways to thicken in such close proximity to lung tissue undergoing emphysematous destruction remains a puzzle that needs to be solved.

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Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice.

Marcus Mall, Barbara Grubb, Jack Harkema … (2004)

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in defective epithelial cAMP-dependent Cl(-) secretion and increased airway Na(+) absorption. The mechanistic links between these altered ion transport processes and the pathogenesis of cystic fibrosis lung disease, however, are unclear. To test the hypothesis that accelerated Na(+) transport alone can produce cystic fibrosis-like lung disease, we generated mice with airway-specific overexpression of epithelial Na(+) channels (ENaC). Here we show that increased airway Na(+) absorption in vivo caused airway surface liquid (ASL) volume depletion, increased mucus concentration, delayed mucus transport and mucus adhesion to airway surfaces. Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation and poor bacterial clearance. We conclude that increasing airway Na(+) absorption initiates cystic fibrosis-like lung disease and produces a model for the study of the pathogenesis and therapy of this disease.

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Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice.

Viswanathan Natarajan, Terry R Medler, W. Hubbard … (2005)

Alveolar cell apoptosis is involved in the pathogenesis of emphysema, a prevalent disease primarily caused by cigarette smoking. We report that ceramide, a second messenger lipid, is a crucial mediator of alveolar destruction in emphysema. Inhibition of enzymes controlling de novo ceramide synthesis prevented alveolar cell apoptosis, oxidative stress and emphysema caused by blockade of the vascular endothelial growth factor (VEGF) receptors in both rats and mice. Emphysema was reproduced with intratracheal instillation of ceramide in naive mice. Excessive ceramide triggers a feed-forward mechanism mediated by activation of secretory acid sphingomyelinase, as suggested by experiments with neutralizing ceramide antibody in mice and with acid sphingomyelinase-deficient fibroblasts. Concomitant augmentation of signaling initiated by a prosurvival metabolite, sphingosine-1-phosphate, prevented lung apoptosis, implying that a balance between ceramide and sphingosine-1-phosphate is required for maintenance of alveolar septal integrity. Finally, increased lung ceramides in individuals with smoking-induced emphysema suggests that ceramide upregulation may be a crucial pathogenic element and a promising target in this disease that currently lacks effective therapies.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 24 August 2012

Volume: 7

Issue: 8

Electronic Location Identifier: e44059

Affiliations

[1 ]Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research, University of Heidelberg, Heidelberg, Germany

[2 ]Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Heidelberg, Germany

[3 ]Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany

[4 ]Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany

Johns Hopkins School of Medicine, United States of America

Author notes

* E-mail: Marcus.Mall@ 123456med.uni-heidelberg.de

Competing Interests: The authors have read the journal's policy and have the following conflicts: MAM is listed on a patent application filed by the University of North Carolina, describing the bENaC-overexpressing mouse (patent number: 7514593; filing date: May 2003). Of note, the bENaC-overexpressing mouse has been deposited at the Jackson Laboratory for general deposition. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors. The other authors (BJ, SH, JS, CS) have declared that no competing interests exist.

Conceived and designed the experiments: BJ MAM. Performed the experiments: BJ SH JS. Analyzed the data: BJ MAM. Wrote the paper: BJ MAM CS.

Article

Publisher ID: PONE-D-12-03548

DOI: 10.1371/journal.pone.0044059

PMC ID: 3427321

PubMed ID: 22937152

SO-VID: 6236a9dc-9944-4a82-a8f8-62081cd58518

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 1 February 2012

Date accepted : 30 July 2012

Page count

Pages: 11

Funding

This study was supported by the German Research Foundation (DFG MA 2081/3-3 and MA 2081/4-1), the Federal Ministry of Education and Research (BMBF German Centre for Lung Research [DZL]), and the European Commission (MEXT-CT-2004–013666). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

CFTR Regulates Early Pathogenesis of Chronic Obstructive Lung Disease in βENaC-Overexpressing Mice

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Abstract

Background

Methods

Results

Conclusions

Related collections

Biomarkers for Inflammatory Lung Disease

Most cited references 37

The pathology of chronic obstructive pulmonary disease.

Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice.

Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice.

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