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Exosomal microRNAs (exo-miRNAs or miRs) have demonstrated diagnostic value in various diseases. However, their diagnostic value in chronic obstructive pulmonary disease (COPD) has yet to be fully established. The purpose of the present study was to screen differentially expressed exo-miRNAs in the plasma of patients with COPD and healthy individuals and to evaluate their potential diagnostic value in COPD. Differentially expressed exo-miRNAs in the plasma of patients with COPD and controls were identified using high-throughput sequencing and confirmed using reverse transcription-quantitative PCR (RT-qPCR). Bioinformatics analysis was then performed to predict the function of the selected exo-miRNAs and their target genes in COPD. After a network model was constructed, linear regression analysis was performed to determine the association between exo-miRNA expression and the clinical characteristics of subjects in a validated cohort (46 COPD cases; 34 matched healthy controls). Receiver operating characteristic curve was subsequently plotted to test the diagnostic value of the candidate biomarkers. The top 20 significantly aberrantly expressed COPD-associated exo-miRNAs were verified using RT-qPCR. Of these, nine were then selected for subsequent analysis, five of which were found to be upregulated (miR-23a, miR-1, miR-574, miR-152 and miR-221) and four of which were downregulated (miR-3158, miR-7706, miR-685 and miR-144). The results of Gene Ontology and KEGG pathway analysis revealed that these miRNAs were mainly involved in certain biological functions, such as metabolic processes, such as galactose metabolism and signaling pathways (PI3K-AKT) associated with COPD. The expression levels of three exo-miRNAs (miR-23a, miR-221 and miR-574) were found to be negatively associated with the forced expiratory volume in the 1st second/forced vital capacity. Furthermore, the area under the curve values of the three exo-miRNAs (miR-23a, miR-221 and miR-574) for COPD diagnosis were 0.776 [95% confidence interval (CI), 0.669-0.882], 0.688 (95% CI, 0.563-0.812) and 0.842 (95% CI, 0.752-0.931), respectively. In conclusion, the three circulating exosomal miRNAs (miR-23a, miR-221 and miR-574) may serve as novel circulating biomarkers for the diagnosis of COPD. These results may also enhance our understanding and provide novel potential treatment options for patients with COPD. [ABSTRACT FROM AUTHOR]