TY - JOUR
T1 - Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema
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
PY - 2014/9/25
Y1 - 2014/9/25
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.
AB - 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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U2 - 10.1371/journal.pone.0106054
DO - 10.1371/journal.pone.0106054
M3 - Article
C2 - 25255451
AN - SCOPUS:84907909005
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 9
M1 - e106054
ER -