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PLoS One. 2014 Sep 25;9(9):e106054. doi: 10.1371/journal.pone.0106054. eCollection 2014.

Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema.

Author information

1
Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
2
Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
3
Department of Pulmonary Diseases, Erasmus MC, Rotterdam, The Netherlands.
4
Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands.
5
Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Bioinformatics, Erasmus MC, Rotterdam, The Netherlands.
6
Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
7
Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
8
Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden, The Netherlands.
9
Department of Pediatric Surgery, Erasmus MC, Rotterdam, The Netherlands.
10
Department of Medical Informatics and Department of Radiology, Erasmus MC, Rotterdam, The Netherlands; Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands.
11
Department of Medical Informatics and Department of Radiology, Erasmus MC, Rotterdam, The Netherlands.
12
Department of Bioinformatics, Erasmus MC, Rotterdam, The Netherlands.
13
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
14
Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.
15
Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.

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.

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.

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.

CONCLUSIONS:

Our experimental data identify genetic susceptibility to extracellular matrix degradation and secondary inflammation as the common mechanisms in both COPD and aneurysm formation.

PMID:
25255451
PMCID:
PMC4177830
DOI:
10.1371/journal.pone.0106054
[Indexed for MEDLINE]
Free PMC Article

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