PracticeUpdate Conference Series: ERS 2018

T hree novel, differentially expressed exosomal microRNAs may be key drivers of the persistent inflammatory response in chronic obstructive pulmonary disease (COPD). Therefore, they are potential targets of future therapies. This finding of an exosome isolation study using exclusion chro- matography was reported at ERS 2018. Tom Wilkinson, MD, of the University of Southampton, UK, and colleagues set out to investigate differentially expressed microR- NAs in exosomes from bronchoalveolar lavage fluid. The goal was to study their effects on inflammatory pathways thought to be key in the pathogenesis of COPD. Exosomes were isolated frombronchoalveolar lavage fluid by size exclusion chromatography from 15 healthy ex-smokers and 20 age- and sex-matched patients withmild tomoderate COPD. Mean forced expiratory volume in 1 second was 79.9% ± 13.9% predicted. Exosomal microRNA was sequenced using the Illumina NextSeq500. Raw data was demultiplexed, trimmed, and aligned to hg19. Negative binomial generalized linear models were used to identify differentially expressed microRNAs between patients with COPD and healthy ex-smokers. An average of 2.8 million reads was obtained for each sample and the average genome mapping rate was 54.5%. A total of 513 microRNAs were detected with a median absolute deviation >1. Of these, 23 microRNAs were differentially expressed between patients with COPD and healthy ex-smokers (false discovery rate < .05). Six exhibited a fold change of >2: ƒ ƒ iR-223-3p Differentially expressed exosomal miRNAs target key inflammatory pathways in COPD. Three Exosomal miRNAs May Be Key Drivers of COPD

Such deregulation targeting a variety of cellular and molecular pathways such as Notch, Wnt, hypoxia-inducible factor-1α, trans- forming growth factor, Kras, and Smad may be involved in the pathogenesis of COPD. Multiple lines of evidence have indicated that extracellular ves- icles such as exosomes may carry a variety of cargos (that is, mRNAs, microRNAs, and proteins) that transfer various cellular and molecular signals to recipient cells. A variety of external factors (that is, smoking and oxidative stress) and internal factors (that is, deregulation of various growth factor ligands, interleukins, and receptor tyrosine kinase) may lead to deregulation of many cellular and molecular pathways and microRNA expression. These events are associated with small and large alterations in molecular and cellular levels and could contribute to the pro- gression of COPD. In addition to their role as therapeutic targets, microRNAs could be employed as prognostic and diagnostic biomarkers in various diseases such as COPD. The latter is a multifactorial disease, and effective diagnostic and therapeutic platforms to treat patients with chronic obstructive pulmonary disease have been sought. It has been shown that the levels of various cytokines (that is, interleukins -6, -8, -10, -17, -12p70, and -1β), cysteinyl-leukotrienes, leukotriene B4, prostaglandin E4, hydrogen peroxide, and 8-iso- prostane may be associated with the pathogenesis of COPD. Despite numerous efforts, effective diagnostic biomarkers remain rare. MicroRNAs have been shown to play a critical role in the pathogenesis of COPD, so it seems that these molecules may be used as prognostic and diagnostic biomarkers for monitoring. In 2015, Dr. Wilkinson’s team assessed the role of exosomal microRNAs in patients with COPD who suffered from skeletal muscle weakness. They found that one exosomal microRNA was upregulated in the serum of patients with COPD. Four exosomal microRNAs were downregulated in the bronchoalveolar fluid of patients with COPD. These microRNAs may exert their effects via targeting of many genes including S6K involved in the mTORC1 signaling pathway. This pathway serves as a key regulator of skeletal muscle wasting. The results indicated that exosomal microRNAs play a critical role in skeletal muscle wasting in patients with COPD and may be used as diagnostic and prognostic biomarkers for detection, treatment, and monitoring. Dr. Wilkinson concluded that these novel, differentially expressed, exosomal microRNAs may be key drivers of the persistent inflam- matory response in COPD. They are therefore potential targets of future therapies.

ƒ ƒ miR-223-5p ƒ ƒ miR-338-3p ƒ ƒ miR-1469 ƒ ƒ miR-204-5p ƒ ƒ miR-618

Kyoto Encyclopedia of Genes and Genomes pathway analysis identified disease relevant inflammatory pathways (tumor necrosis factor α, nuclear factor κ-light-chain-enhancer of activated β cells, andmitogen-activated protein kinase signaling) regulated by these microRNAs. Future in vitro modeling will validate these findings. Exosomes are nanosized vesicles that transport microRNA and alter gene expression in recipient cells. Among various bio- markers, microRNAs have emerged as new biomarkers for the prognosis and diagnosis of COPD. Deregulation of microRNAs is associated with the initiation and progression of several diseases such as stroke, cardiovascular diseases, diabetes, cancer, and inflammatory diseases.

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ERS 2018 • PRACTICEUPDATE CONFERENCE SERIES