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Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema.
- Source :
-
PloS one [PLoS One] 2014 Sep 25; Vol. 9 (9), pp. e106054. Date of Electronic Publication: 2014 Sep 25 (Print Publication: 2014). - Publication Year :
- 2014
-
Abstract
- Background: In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined development of pulmonary emphysema and vascular disease.<br />Methods: We first determined the prevalence of chronic obstructive pulmonary disease in a clinical cohort of aortic aneurysms patients and arterial occlusive disease patients. Subsequently, we used a combined approach comprising pathological, functional, molecular imaging, immunological and gene expression analysis to reveal the sequence of events that culminates in pulmonary emphysema in aneurysmal Fibulin-4 deficient (Fibulin-4(R)) mice.<br />Results: Here we show that COPD is significantly more prevalent in aneurysm patients compared to arterial occlusive disease patients, independent of smoking, other clinical risk factors and inflammation. In addition, we demonstrate that aneurysmal Fibulin-4(R/R) mice display severe developmental lung emphysema, whereas Fibulin-4(+/R) mice acquire alveolar breakdown with age and upon infectious stress. This vicious circle is further exacerbated by the diminished antiprotease capacity of the lungs and ultimately results in the development of pulmonary emphysema.<br />Conclusions: Our experimental data identify genetic susceptibility to extracellular matrix degradation and secondary inflammation as the common mechanisms in both COPD and aneurysm formation.
- Subjects :
- Aged
Animals
Aorta drug effects
Aorta metabolism
Aorta pathology
Aortic Aneurysm metabolism
Cohort Studies
Disease Susceptibility
Down-Regulation drug effects
Female
Humans
Lipopolysaccharides pharmacology
Lung drug effects
Lung immunology
Lung metabolism
Lung pathology
Male
Matrix Metalloproteinases metabolism
Mice
Neutrophils enzymology
Pancreatic Elastase metabolism
Pulmonary Alveoli drug effects
Pulmonary Alveoli metabolism
Pulmonary Alveoli pathology
Signal Transduction drug effects
Transforming Growth Factor beta metabolism
alpha 1-Antitrypsin metabolism
Aortic Aneurysm complications
Aortic Aneurysm pathology
Extracellular Matrix metabolism
Extracellular Matrix Proteins deficiency
Extracellular Matrix Proteins metabolism
Pulmonary Emphysema complications
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25255451
- Full Text :
- https://doi.org/10.1371/journal.pone.0106054