Late Breaking Abstract - Differentially expressed exosomal miRNAs target key inflammatory pathways in COPD.

Rationale: COPD is characterised by chronic airway inflammation, which persists beyond smoking cessation. The underlying mechanisms for this are unclear and aberrant cellular signalling may be key. Exosomes are nanosized vesicles, which transport miRNA and alter gene expression in recipient cells. We investigated the differentially expressed miRNAs in bronchoalveolar lavage fluid (BALF) exosomes, with the aim of studying their effects on inflammatory pathways thought to be key to COPD pathogenesis. Methods: Exosomes were isolated from BALF by size exclusion chromatography from 15 healthy ex-smokers and 20 age and sex matched mild-moderate COPD patients with a mean FEV1 79.9% predicted (SD 13.9%). Exosomal miRNA was sequenced using the Illumina NextSeq500. Raw data was de-multiplexed, trimmed and aligned to hg19. Negative binomial generalised linear models were used to identify differentially expressed miRNAs between COPD and healthy ex-smokers. Results: An average of 2.8 million reads were obtained for each sample and the average genome mapping rate was 54.5%. 513 miRNA were detected with a median absolute deviation greater than one. Of these, 23 miRNAs were differentially expressed between COPD and healthy ex-smokers (FDR 2: miR-223-3p, miR-223-5p, miR-338-3p, miR-1469, miR-204-5p and miR-618. KEGG pathway analysis identified disease relevant inflammatory pathways (TNFα, NF-κβ, and MAPK signalling) regulated by these miRNAs. Future in vitro modelling will validate these findings. Conclusion: These novel differentially expressed exosomal miRNA may be key drivers of the persistent inflammatory response in COPD and therefore are potential targets for future therapies.