Integrated miRNA-mRNA network analysis identifies miR-182-5p as a potential regulator in COPD pathogenesis

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide and currently lacks effective disease-modifying therapies. Extracellular vesicles (EVs) are key mediators of intercellular communication and transport biologically active cargo, including microRNAs (miRNAs). We previously identified 8 differentially expressed EV miRNA (miR-223-3p, miR-2110, miR-182-5p, miR-200b-5p, miR-625-3p, miR-204-5p, miR-138-5p and miR-338-3p) that were differentially expressed in individuals with COPD compared with healthy volunteer ex-smoker controls (HV-ES). This study aimed to identify miRNA-mRNA interactions in diseased lung epithelium that may contribute to COPD pathogenesis.

Gene expression was quantified by RNA sequencing of epithelial brushings obtained from 24 subjects with COPD and 20 HV-ES. In silico analyses were performed to identify target genes of the previously identified EV-derived miRNAs isolated from the same individuals. MiRNA-mRNA interactions were examined using negative correlation analysis and network-based approaches, and enrichment of biological processes was assessed using Cytoscape. Associations between computer tomography (CT) disease probability measures (DPM) and gene expression were assessed using Spearman correlation across the pooled cohort.

A total of 191 genes were differentially expressed in epithelial brushings from subjects with COPD compared with HV-ES. In silico analysis identified 121 miRNA-mRNA interactions involving these genes and the EV-associated miRNAs. Network analysis revealed miR-182-5p as a central hub, targeting multiple highly differentially expressed genes (DEGs). Expression of these DEGs correlated with CT DPM of emphysema and small airways disease (SAD). Exploratory pathway analyses suggested potential trends toward coordinated network regulation involving metabolic and immune -related processes; however, no biological processes remained significant after correction for multiple testing.

These findings highlight a potential role for EV-derived miRNA-mRNA regulatory networks in COPD pathogenesis, with miR-182-5p emerging as a putative regulator within this network. While exploratory analyses suggested possible associations with metabolic and immune-related pathways, these did not withstand multiple testing correction and should therefore be interpreted as hypothesis-generating. These findings support further mechanistic investigation of EV-derived miRNA-mRNA regulatory networks in COPD and may help inform future translational studies exploring their biological relevance.