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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Aorta / drug effects
  • Aorta / metabolism
  • Aorta / pathology
  • Aortic Aneurysm / complications*
  • Aortic Aneurysm / metabolism
  • Aortic Aneurysm / pathology*
  • Cohort Studies
  • Disease Susceptibility
  • Down-Regulation / drug effects
  • Extracellular Matrix / metabolism*
  • Extracellular Matrix Proteins / deficiency*
  • Extracellular Matrix Proteins / metabolism*
  • 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
  • Pulmonary Emphysema / complications*
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta / metabolism
  • alpha 1-Antitrypsin / metabolism


  • EFEMP2 protein, human
  • Extracellular Matrix Proteins
  • Lipopolysaccharides
  • SERPINA1 protein, human
  • Transforming Growth Factor beta
  • alpha 1-Antitrypsin
  • Pancreatic Elastase
  • Matrix Metalloproteinases

Grant support

This work was supported by the ‘Lijf en Leven’ grant (2008): ‘Early detection and diagnosis of aneurysms and heart valve abnormalities’ (to JE and PvH). LH is supported by the Alp d’HuZes/Bas Mulder award 2011 (UL 2011-5051). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.