PloS one · 2014
Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema.
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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
Аннотация
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.
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.
Предметные рубрики MeSH
AgedAnimalsAortaAortic AneurysmCohort StudiesDisease SusceptibilityDown-RegulationExtracellular MatrixExtracellular Matrix ProteinsFemaleHumansLipopolysaccharidesLungMaleMatrix MetalloproteinasesMiceNeutrophilsPancreatic ElastasePulmonary AlveoliPulmonary EmphysemaSignal TransductionTransforming Growth Factor betaalpha 1-Antitrypsin