1. Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema.
- Author
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Ramnath NW, van de Luijtgaarden KM, van der Pluijm I, van Nimwegen M, van Heijningen PM, Swagemakers SM, van Thiel BS, Ridwan RY, van Vliet N, Vermeij M, Hawinkels LJ, de Munck A, Dzyubachyk O, Meijering E, van der Spek P, Rottier R, Yanagisawa H, Hendriks RW, Kanaar R, Rouwet EV, Kleinjan A, and Essers J
- Subjects
- Aged, Animals, Aorta drug effects, Aorta metabolism, Aorta pathology, Aortic Aneurysm metabolism, Cohort Studies, Disease Susceptibility, Down-Regulation drug effects, 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, Signal Transduction drug effects, Transforming Growth Factor beta metabolism, alpha 1-Antitrypsin metabolism, Aortic Aneurysm complications, Aortic Aneurysm pathology, Extracellular Matrix metabolism, Extracellular Matrix Proteins deficiency, Extracellular Matrix Proteins metabolism, Pulmonary Emphysema complications
- 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-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.
- Published
- 2014
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