title: MicroRNA Profiling Reveals a Role for MicroRNA-218-5p in the Pathogenesis of Chronic Obstructive Pulmonary Disease.
abstract: Aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis.
  
  
  
  To identify dysregulated miRNAs in lung tissue of patients with chronic obstructive pulmonary disease (COPD).
  
  
  
  We performed miRNA and mRNA profiling using high throughput stem-loop reverse-transcriptase quantitative polymerase chain reaction and mRNA microarray, respectively, on lung tissue of 30 patients (screening cohort) encompassing 8 never-smokers, 10 smokers without airflow limitation, and 12 smokers with COPD. Differential expression of miRNA-218-5p (miR-218-5p) was validated by reverse-transcriptase quantitative polymerase chain reaction in an independent cohort of 71 patients, an in vivo murine model of COPD, and primary human bronchial epithelial cells. Localization of miR-218-5p was assessed by in situ hybridization. In vitro and in vivo perturbation of miR-218-5p combined with RNA sequencing and gene set enrichment analysis was used to elucidate its functional role in COPD pathogenesis.
  
  
  
  Several miRNAs were differentially expressed among the different patient groups. Interestingly, miR-218-5p was significantly down-regulated in smokers without airflow limitation and in patients with COPD compared with never-smokers. Decreased pulmonary expression of miR-218-5p was validated in an independent validation cohort, in cigarette smoke-exposed mice, and in human bronchial epithelial cells. Importantly, expression of miR-218-5p strongly correlated with airway obstruction. Furthermore, cellular localization of miR-218-5p in human and murine lung revealed highest expression of miR-218-5p in the bronchial airway epithelium. Perturbation experiments with a miR-218-5p mimic or inhibitor demonstrated a protective role of miR-218-5p in cigarette smoke-induced inflammation and COPD.
  
  
  
  We highlight a role for miR-218-5p in the pathogenesis of COPD.
authors.affiliation: 1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Griet
authors.initials: G
authors.lastname: Conickx
authors.affiliation: 2 Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.affiliation: 2 Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Francisco
authors.initials: F
authors.lastname: Avila Cobos
authors.affiliation: 1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Fien M
authors.initials: FM
authors.lastname: Verhamme
authors.affiliation: 1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Tania
authors.initials: T
authors.lastname: Maes
authors.affiliation: 3 Department of Clinical and Experimental Medicine, Laboratory for Respiratory Diseases, Lung Transplantation Unit, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: Bart M
authors.initials: BM
authors.lastname: Vanaudenaerde
authors.affiliation: 1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Leen J M
authors.initials: LJ
authors.lastname: Seys
authors.affiliation: 1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Lies
authors.initials: L
authors.lastname: Lahousse
authors.affiliation: 4 Priority Research Centres for Asthma and Respiratory Diseases and Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia; and.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Kim
authors.affiliation: 4 Priority Research Centres for Asthma and Respiratory Diseases and Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia; and.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Hsu
authors.affiliation: 4 Priority Research Centres for Asthma and Respiratory Diseases and Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia; and.|5 Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Wark
authors.affiliation: 4 Priority Research Centres for Asthma and Respiratory Diseases and Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia; and.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: 1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Guy F
authors.initials: GF
authors.lastname: Joos
authors.affiliation: 2 Center for Medical Genetics, Ghent University, Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.affiliation: 1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Ken R
authors.identifier: 0000-0001-5906-4605
authors.initials: KR
authors.lastname: Bracke
authors.affiliation: 1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Guy G
authors.identifier: 0000-0001-7021-8505
authors.initials: GG
authors.lastname: Brusselle
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001980:Bronchi / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C547471:MIRN218 microRNA, human; D035683:MicroRNAs
keywords: chronic obstructive pulmonary disease; lung; microRNA; microRNA-218