• Griet Conickx, Pieter Mestdagh, Francisco Avila Cobos, Fien M Verhamme, Tania Maes, Bart M Vanaudenaerde, Leen J M Seys, Lies Lahousse, Richard Y Kim, Alan C Hsu, Peter A Wark, Philip M Hansbro, Guy F Joos, Jo Vandesompele, Ken R Bracke, and Guy G Brusselle.
• 1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
• Am. J. Respir. Crit. Care Med. 2017 Jan 1; 195 (1): 43-56.

RationaleAberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis.ObjectivesTo identify dysregulated miRNAs in lung tissue of patients with chronic obstructive pulmonary disease (COPD).MethodsWe 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 ResultsSeveral 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.ConclusionsWe highlight a role for miR-218-5p in the pathogenesis of COPD.

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