Griet Conickx1, Pieter Mestdagh2, Francisco Avila Cobos2, Fien M Verhamme1, Tania Maes1, Bart M Vanaudenaerde3, Leen J M Seys1, Lies Lahousse1, Richard Y Kim4, Alan C Hsu4, Peter A Wark4,5, Philip M Hansbro4, Guy F Joos1, Jo Vandesompele2, Ken R Bracke1, Guy G Brusselle1. 1. 1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium. 2. 2 Center for Medical Genetics, Ghent University, Ghent, Belgium. 3. 3 Department of Clinical and Experimental Medicine, Laboratory for Respiratory Diseases, Lung Transplantation Unit, KU Leuven-University of Leuven, Leuven, Belgium. 4. 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. 5 Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia.
Abstract
RATIONALE: Aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis. OBJECTIVES: To identify dysregulated miRNAs in lung tissue of patients with chronic obstructive pulmonary disease (COPD). METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: We highlight a role for miR-218-5p in the pathogenesis of COPD.
RATIONALE: Aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis. OBJECTIVES: To identify dysregulated miRNAs in lung tissue of patients with chronic obstructive pulmonary disease (COPD). METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: We highlight a role for miR-218-5p in the pathogenesis of COPD.
Authors: Alan C-Y Hsu; Kamal Dua; Malcolm R Starkey; Tatt-Jhong Haw; Prema M Nair; Kristy Nichol; Nathan Zammit; Shane T Grey; Katherine J Baines; Paul S Foster; Philip M Hansbro; Peter A Wark Journal: JCI Insight Date: 2017-04-06
Authors: Sébastien Bonnet; Olivier Boucherat; Roxane Paulin; Danchen Wu; Charles C T Hindmarch; Stephen L Archer; Rui Song; Joseph B Moore; Steeve Provencher; Lubo Zhang; Shizuka Uchida Journal: Am J Physiol Cell Physiol Date: 2019-09-04 Impact factor: 4.249
Authors: Gang Liu; Marion A Cooley; Andrew G Jarnicki; Theo Borghuis; Prema M Nair; Gavin Tjin; Alan C Hsu; Tatt Jhong Haw; Michael Fricker; Celeste L Harrison; Bernadette Jones; Nicole G Hansbro; Peter A Wark; Jay C Horvat; W Scott Argraves; Brian G Oliver; Darryl A Knight; Janette K Burgess; Philip M Hansbro Journal: JCI Insight Date: 2019-07-25
Authors: E G De Smet; H P Van Eeckhoutte; F Avila Cobos; E Blomme; F M Verhamme; S Provoost; S E Verleden; K Venken; T Maes; G F Joos; P Mestdagh; G G Brusselle; K R Bracke Journal: Mucosal Immunol Date: 2019-12-09 Impact factor: 7.313