The targets and functions of lung-derived extracellular vesicle microRNA in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterised by chronic airway inflammation, which is dependent upon a complex network of intercellular communication between the damaged airway epithelium and the immune system. Extracellular vesicles (EVs) are novel major signalling mediators between cells, and shuttle cargo such as micro RNA (miRNA) in health and disease. This thesis examines the role of EV miRNA regulation of inflammatory signalling pathways in COPD.
EVs were isolated from bronchoalveolar lavage fluid (BALF), and epithelial brushings were taken from the same patients with COPD and healthy controls. RNA sequencing was used to quantify EV miRNA expression and gene expression in epithelial brushings. Negative binomial models were used to identify differentially expressed miRNA and genes in patients with COPD, and a combination of bioinformatic approaches were used to identify the biologically significant interactions between these miRNA and genes. Further analysis assessed the predictive ability of the differentially expressed miRNA in discriminating between health and disease and their relationship with inflammatory endotypes in COPD.
Differential miRNA expression was observed in BALF EVs from patients with COPD compared to healthy ex-smokers. Specifically, five miRNA were found to be up-regulated in COPD (miR-2110, miR-182-5p, miR-223-3p, miR-200b-5p and miR-625-3p) and three miRNA were down-regulated in COPD (miR-338-3p, miR-138-5p and miR-204-5p). In silico analysis demonstrated these differentially expressed miRNA targeted differentially expressed genes in epithelial brushings in the same patients. These miRNA-gene expression interactions may have a significant impact on key inflammatory pathways in COPD. In addition, lung-derived EV miRNA were a strong predictor of disease presence. Moreover, specific EV miRNA correlated with expression of inflammatory cells within the airways of COPD patients, which may provide novel insights into distinct inflammatory endotypic disease mechanisms.
..In summary, the findings from this thesis suggest that lung-derived EV miRNA may regulate gene expression in COPD leading to aberrant inflammatory signalling. Furthermore, EV miRNA may provide a novel diagnostic opportunity to detect early disease presence in COPD, and give further insights into the underlying endotypic mechanisms of disease, whereby EV miRNA could help future treatment stratification.

More information

Identifiers

ORCID for Karl Staples: orcid.org/0000-0003-3844-6457

Catalogue record

Export record