title: Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema.
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.
authors.affiliation: Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Natasja W M
authors.initials: NW
authors.lastname: Ramnath
authors.affiliation: Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Koen M
authors.initials: KM
authors.lastname: van de Luijtgaarden
authors.affiliation: Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Pluijm
authors.affiliation: Department of Pulmonary Diseases, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: van Nimwegen
authors.affiliation: Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Paula M
authors.initials: PM
authors.lastname: van Heijningen
authors.affiliation: Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Bioinformatics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Sigrid M A
authors.initials: SM
authors.lastname: Swagemakers
authors.affiliation: Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Bibi S
authors.initials: BS
authors.lastname: van Thiel
authors.affiliation: Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands; Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ruziedi Y
authors.initials: RY
authors.lastname: Ridwan
authors.affiliation: Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: van Vliet
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Vermeij
authors.affiliation: Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden, The Netherlands.
authors.forename: Luuk J A C
authors.initials: LJ
authors.lastname: Hawinkels
authors.affiliation: Department of Pediatric Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Anne
authors.initials: A
authors.lastname: de Munck
authors.affiliation: Department of Medical Informatics and Department of Radiology, Erasmus MC, Rotterdam, The Netherlands; Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Oleh
authors.initials: O
authors.lastname: Dzyubachyk
authors.affiliation: Department of Medical Informatics and Department of Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Meijering
authors.affiliation: Department of Bioinformatics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van der Spek
authors.affiliation: Department of Pediatric Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Robbert
authors.initials: R
authors.lastname: Rottier
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yanagisawa
authors.affiliation: Department of Pulmonary Diseases, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
authors.affiliation: Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Roland
authors.initials: R
authors.lastname: Kanaar
authors.affiliation: Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ellen V
authors.initials: EV
authors.lastname: Rouwet
authors.affiliation: Department of Pulmonary Diseases, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Kleinjan
authors.affiliation: Department of Genetics, Cancer Genomics Centre, Erasmus MC, Rotterdam, The Netherlands; Department of Radiation Oncology, Erasmus MC, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Essers
mesh_terms: D000368:Aged; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001014:Aortic Aneurysm / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D015331:Cohort Studies; D004198:Disease Susceptibility; D015536:Down-Regulation / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000201:enzymology; D010196:Pancreatic Elastase / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000150:complications*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000378:metabolism
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; D008070:Lipopolysaccharides; C043392:SERPINA1 protein, human; D016212:Transforming Growth Factor beta; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase; D020782:Matrix Metalloproteinases