Airway mucus obstruction triggers macrophage activation and matrix metalloproteinase 12-dependent emphysema
(2014) In American Journal of Respiratory Cell and Molecular Biology 51(5). p.709-720- Abstract
Whereas cigarette smoking remains the main risk factor for emphysema, recent studies in β-epithelial Na+ channel-transgenic (βENaC-Tg) mice demonstrated that airway surface dehydration, a key pathophysiological mechanism in cystic fibrosis (CF), caused emphysema in the absence of cigarette smoke exposure. However, the underlying mechanisms remain unknown. The aim of this study was to elucidate mechanisms of emphysema formation triggered by airway surface dehydration. We therefore used expression profiling, genetic and pharmacological inhibition, Foerster resonance energy transfer (FRET)-based activity assays, and genetic association studies to identify and validate emphysema candidate genes in βENaC-Tg mice and patients with... (More)
Whereas cigarette smoking remains the main risk factor for emphysema, recent studies in β-epithelial Na+ channel-transgenic (βENaC-Tg) mice demonstrated that airway surface dehydration, a key pathophysiological mechanism in cystic fibrosis (CF), caused emphysema in the absence of cigarette smoke exposure. However, the underlying mechanisms remain unknown. The aim of this study was to elucidate mechanisms of emphysema formation triggered by airway surface dehydration. We therefore used expression profiling, genetic and pharmacological inhibition, Foerster resonance energy transfer (FRET)-based activity assays, and genetic association studies to identify and validate emphysema candidate genes in βENaC-Tg mice and patients with CF. We identified matrix metalloproteinase 12 (Mmp12) as a highly upregulated gene in lungs from βENaC-Tg mice, and demonstrate that elevated Mmp12 expression was associated with progressive emphysema formation, which was reduced by genetic deletion and pharmacological inhibition of MMP12 in vivo. By using FRET reporters, we show that MMP12 activity was elevated on the surface of airway macrophages in bronchoalveolar lavage from βENaC-Tg mice and patients with CF. Furthermore, we demonstrate that a functional polymorphism in MMP12 (rs2276109) was associated with severity of lung disease in CF. Our results suggest that MMP12 released by macrophages activated on dehydrated airway surfaces may play an important role in emphysema formation in the absence of cigarette smoke exposure, and may serve as a therapeutic target in CF and potentially other chronic lung diseases associated with airway mucus dehydration and obstruction.
(Less)
- author
- publishing date
- 2014-11-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Airway surface liquid, Chronic obstructive pulmonary disease, Cystic fibrosis, Inflammation, Mucus
- in
- American Journal of Respiratory Cell and Molecular Biology
- volume
- 51
- issue
- 5
- pages
- 709 - 720
- publisher
- American Thoracic Society
- external identifiers
-
- scopus:84914143169
- pmid:24828142
- ISSN
- 1044-1549
- DOI
- 10.1165/rcmb.2013-0407OC
- language
- English
- LU publication?
- no
- additional info
- Publisher Copyright: Copyright © 2014 by the American Thoracic Society.
- id
- 061980cc-113e-4f41-a60b-a63c3e4606bb
- date added to LUP
- 2024-04-29 16:21:45
- date last changed
- 2024-05-13 17:35:45
@article{061980cc-113e-4f41-a60b-a63c3e4606bb,
abstract = {{<p>Whereas cigarette smoking remains the main risk factor for emphysema, recent studies in β-epithelial Na<sup>+</sup> channel-transgenic (βENaC-Tg) mice demonstrated that airway surface dehydration, a key pathophysiological mechanism in cystic fibrosis (CF), caused emphysema in the absence of cigarette smoke exposure. However, the underlying mechanisms remain unknown. The aim of this study was to elucidate mechanisms of emphysema formation triggered by airway surface dehydration. We therefore used expression profiling, genetic and pharmacological inhibition, Foerster resonance energy transfer (FRET)-based activity assays, and genetic association studies to identify and validate emphysema candidate genes in βENaC-Tg mice and patients with CF. We identified matrix metalloproteinase 12 (Mmp12) as a highly upregulated gene in lungs from βENaC-Tg mice, and demonstrate that elevated Mmp12 expression was associated with progressive emphysema formation, which was reduced by genetic deletion and pharmacological inhibition of MMP12 in vivo. By using FRET reporters, we show that MMP12 activity was elevated on the surface of airway macrophages in bronchoalveolar lavage from βENaC-Tg mice and patients with CF. Furthermore, we demonstrate that a functional polymorphism in MMP12 (rs2276109) was associated with severity of lung disease in CF. Our results suggest that MMP12 released by macrophages activated on dehydrated airway surfaces may play an important role in emphysema formation in the absence of cigarette smoke exposure, and may serve as a therapeutic target in CF and potentially other chronic lung diseases associated with airway mucus dehydration and obstruction.</p>}},
author = {{Trojanek, Joanna B. and Cobos-Correa, Amanda and Diemer, Stefanie and Kormann, Michael and Schubert, Susanne C. and Zhou-Suckow, Zhe and Agrawal, Raman and Duerr, Julia and Wagner, Claudius J. and Schatterny, Jolanthe and Hirtz, Stephanie and Sommerburg, Olaf and Hartl, Dominik and Schultz, Carsten and Mall, Marcus A.}},
issn = {{1044-1549}},
keywords = {{Airway surface liquid; Chronic obstructive pulmonary disease; Cystic fibrosis; Inflammation; Mucus}},
language = {{eng}},
month = {{11}},
number = {{5}},
pages = {{709--720}},
publisher = {{American Thoracic Society}},
series = {{American Journal of Respiratory Cell and Molecular Biology}},
title = {{Airway mucus obstruction triggers macrophage activation and matrix metalloproteinase 12-dependent emphysema}},
url = {{http://dx.doi.org/10.1165/rcmb.2013-0407OC}},
doi = {{10.1165/rcmb.2013-0407OC}},
volume = {{51}},
year = {{2014}},
}