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

Natasja W M Ramnath, Koen M. Van De Luijtgaarden, Ingrid Van Der Pluijm, Menno Van Nimwegen, Paula M. Van Heijningen, Sigrid M A Swagemakers, Bibi S. Van Thiel, Ruziedi Y. Ridwan, Nicole Van Vliet, Marcel Vermeij, Luuk J A C Hawinkels, Anne De Munck, Oleh Dzyubachyk, Erik Meijering, Peter Van Der Spek, Robbert Rottier, Hiromi Yanagisawa, Rudi W. Hendriks, Roland Kanaar, Ellen V. RouwetAlex Kleinjan, Jeroen Essers

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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-4R) 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-4R/Rmice display severe developmental lung emphysema, whereas Fibulin-4+/Rmice 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.

Original languageEnglish (US)
Article numbere106054
JournalPloS one
Issue number9
StatePublished - Sep 25 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General


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