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MicroRNA profiling reveals a role for microRNA-218-5p in the pathogenesis of chronic obstructive pulmonary disease
Tijdschriftbijdrage - Tijdschriftartikel
RATIONALE: Since aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis, we aimed to identify dysregulated miRNAs in lung tissue of patients with COPD.METHODS: We performed miRNA and mRNA profiling - using high throughput stem-loop RT-qPCR 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 microRNA-218-5p (miR-218-5p) was validated by RT-qPCR in an independent cohort of 71 patients, an in vivo murine model of COPD, and primary human bronchial epithelial cells (HBECs). 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 both smokers without airflow limitation and in patients with COPD, compared to never smokers. Decreased pulmonary expression of miR-218-5p was validated in an independent validation cohort, in cigarette smoke-exposed mice and in HBECs. 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.
Tijdschrift: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Pagina's: 43 - 56
Jaar van publicatie:2017