Corry-Anke Brandsma1, Maarten van den Berge2, Dirkje S Postma2, Marnix R Jonker1, Sharon Brouwer1, Peter D Paré3, Don D Sin3, Yohan Bossé4, Michel Laviolette5, Juha Karjalainen6, Rudolf S N Fehrmann6, David C Nickle7, Ke Hao7, Anita I R Spanjer8, Wim Timens1, Lude Franke6. 1. 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. 2. 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. 3. The University of British Columbia, Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, Canada Respiratory Division, University of British Columbia, Vancouver, Canada. 4. Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada Department of Molecular Medicine, Laval University, Québec, Canada. 5. Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada. 6. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 7. Merck Research Laboratories, Boston, Massachusetts, USA. 8. 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.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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