title: A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is a progressive, incurable lung disease characterised by abnormal tissue repair causing emphysema and small airways fibrosis. Since current therapy cannot modify this abnormal repair, it is crucial to unravel its underlying molecular mechanisms. Unbiased analysis of genome-wide gene expression profiles in lung tissue provides a powerful tool to investigate this.
  
  
  METHODS
  We performed genome-wide gene expression profiling in 581 lung tissue samples from current and ex-smokers with (n=311) and without COPD (n=270). Subsequently, quantitative PCR, western blot and immunohistochemical analyses were performed to validate our main findings.
  
  
  RESULTS
  112 genes were found to be upregulated in patients with COPD compared with controls, whereas 61 genes were downregulated. Among the most upregulated genes were fibulin-5 (FBLN5), elastin (ELN), latent transforming growth factor β binding protein 2 (LTBP2) and microfibrillar associated protein 4 (MFAP4), all implicated in elastogenesis. Our gene expression findings were validated at mRNA and protein level. We demonstrated higher ELN gene expression in COPD lung tissue and similar trends for FBLN5 and MFAP4, and negative correlations with lung function. FBLN5 protein levels were increased in COPD lung tissue and cleaved, possibly non-functional FBLN5 protein was present. Strong coexpression of FBLN5, ELN, LTBP2 and MFAP4 in lung tissue and in silico analysis indicated cofunctionality of these genes. Finally, colocalisation of FBLN5, MFAP4 and LTBP2 with elastic fibres was demonstrated in lung tissue.
  
  
  CONCLUSIONS
  We identified a clear gene signature for elastogenesis in COPD and propose FBLN5 as a novel player in tissue repair in COPD.
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
authors.forename: Corry-Anke
authors.initials: CA
authors.lastname: Brandsma
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
authors.forename: Marnix R
authors.initials: MR
authors.lastname: Jonker
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
authors.forename: Sharon
authors.initials: S
authors.lastname: Brouwer
authors.affiliation: The University of British Columbia, Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, Canada Respiratory Division, University of British Columbia, Vancouver, Canada.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.affiliation: The University of British Columbia, Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, Canada Respiratory Division, University of British Columbia, Vancouver, Canada.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada Department of Molecular Medicine, Laval University, Québec, Canada.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Laviolette
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Juha
authors.initials: J
authors.lastname: Karjalainen
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rudolf S N
authors.initials: RS
authors.lastname: Fehrmann
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Nickle
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.
authors.forename: Anita I R
authors.initials: AI
authors.lastname: Spanjer
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
mesh_terms: D000368:Aged; D015153:Blotting, Western; D004548:Elasticity; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; D012333:RNA, Messenger
keywords: COPD ÀÜ Mechanisms; Emphysema