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 journalArticle

13 Citations (Scopus)

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-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
Volume9
Issue number9
DOIs
StatePublished - Sep 25 2014

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aneurysm
Pulmonary diseases
pulmonary emphysema
Emphysema
extracellular matrix
Pulmonary Emphysema
respiratory tract diseases
Chronic Obstructive Pulmonary Disease
Extracellular Matrix
lungs
Lung
Arterial Occlusive Diseases
Defects
Aortic Aneurysm
mice
Aneurysm
inflammation
Inflammation
Lung Volume Measurements
Molecular imaging

ASJC Scopus subject areas

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

Cite this

Ramnath, N. W. M., Van De Luijtgaarden, K. M., Van Der Pluijm, I., Van Nimwegen, M., Van Heijningen, P. M., Swagemakers, S. M. A., ... Essers, J. (2014). Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema. PLoS One, 9(9), [e106054]. https://doi.org/10.1371/journal.pone.0106054

Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema. / Ramnath, Natasja W M; Van De Luijtgaarden, Koen M.; Van Der Pluijm, Ingrid; Van Nimwegen, Menno; Van Heijningen, Paula M.; Swagemakers, Sigrid M A; Van Thiel, Bibi S.; Ridwan, Ruziedi Y.; Van Vliet, Nicole; Vermeij, Marcel; Hawinkels, Luuk J A C; De Munck, Anne; Dzyubachyk, Oleh; Meijering, Erik; Van Der Spek, Peter; Rottier, Robbert; Yanagisawa, Hiromi; Hendriks, Rudi W.; Kanaar, Roland; Rouwet, Ellen V.; Kleinjan, Alex; Essers, Jeroen.

In: PLoS One, Vol. 9, No. 9, e106054, 25.09.2014.

Research output: Contribution to journalArticle

Ramnath, NWM, Van De Luijtgaarden, KM, Van Der Pluijm, I, Van Nimwegen, M, Van Heijningen, PM, Swagemakers, SMA, Van Thiel, BS, Ridwan, RY, Van Vliet, N, Vermeij, M, Hawinkels, LJAC, De Munck, A, Dzyubachyk, O, Meijering, E, Van Der Spek, P, Rottier, R, Yanagisawa, H, Hendriks, RW, Kanaar, R, Rouwet, EV, Kleinjan, A & Essers, J 2014, 'Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema', PLoS One, vol. 9, no. 9, e106054. https://doi.org/10.1371/journal.pone.0106054
Ramnath NWM, Van De Luijtgaarden KM, Van Der Pluijm I, Van Nimwegen M, Van Heijningen PM, Swagemakers SMA et al. Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema. PLoS One. 2014 Sep 25;9(9). e106054. https://doi.org/10.1371/journal.pone.0106054
Ramnath, Natasja W M ; Van De Luijtgaarden, Koen M. ; Van Der Pluijm, Ingrid ; Van Nimwegen, Menno ; Van Heijningen, Paula M. ; Swagemakers, Sigrid M A ; Van Thiel, Bibi S. ; Ridwan, Ruziedi Y. ; Van Vliet, Nicole ; Vermeij, Marcel ; Hawinkels, Luuk J A C ; De Munck, Anne ; Dzyubachyk, Oleh ; Meijering, Erik ; Van Der Spek, Peter ; Rottier, Robbert ; Yanagisawa, Hiromi ; Hendriks, Rudi W. ; Kanaar, Roland ; Rouwet, Ellen V. ; Kleinjan, Alex ; Essers, Jeroen. / Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema. In: PLoS One. 2014 ; Vol. 9, No. 9.
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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-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.",
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AU - Ramnath, Natasja W M

AU - Van De Luijtgaarden, Koen M.

AU - Van Der Pluijm, Ingrid

AU - Van Nimwegen, Menno

AU - Van Heijningen, Paula M.

AU - Swagemakers, Sigrid M A

AU - Van Thiel, Bibi S.

AU - Ridwan, Ruziedi Y.

AU - Van Vliet, Nicole

AU - Vermeij, Marcel

AU - Hawinkels, Luuk J A C

AU - De Munck, Anne

AU - Dzyubachyk, Oleh

AU - Meijering, Erik

AU - Van Der Spek, Peter

AU - Rottier, Robbert

AU - Yanagisawa, Hiromi

AU - Hendriks, Rudi W.

AU - Kanaar, Roland

AU - Rouwet, Ellen V.

AU - Kleinjan, Alex

AU - Essers, Jeroen

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N2 - 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.

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