Ikari, JunNelson, Amy J.Obaid, JannahGiron-Martinez, AlvaroIkari, KumikoMakino, FumihikoIwasawa, ShunichiroGunji, YokoFarid, MahaWang, XingqiBasma, HeshamDemeo, DawnFeghali-Bostwick, CarolHolz, OlafRabe, KlausLiu, XiangdeRennard, Stephen I.2017-12-052017Ikari, J., A. J. Nelson, J. Obaid, A. Giron-Martinez, K. Ikari, F. Makino, S. Iwasawa, et al. 2017. “Reduced microRNA-503 expression augments lung fibroblast VEGF production in chronic obstructive pulmonary disease.” PLoS ONE 12 (9): e0184039. doi:10.1371/journal.pone.0184039. http://dx.doi.org/10.1371/journal.pone.0184039.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34491850Alterations in microRNA (miRNA) expression may contribute to COPD pathogenesis. In COPD, lung fibroblast repair functions are altered in multiple ways, including extracellular mediator release. Our prior study revealed miR-503 expression is decreased in COPD lung fibroblasts, although the exact role played by miR-503 is undetermined. The current study examined a role of miR-503 in cytokine, growth factor and fibronectin production by lung fibroblasts from patients with and without COPD. Primary adult lung fibroblasts were isolated from patients with or without COPD. MiR-503 expression and interleukin (IL)-6, -8, PGE2, HGF, KGF, VEGF and fibronectin release were examined with or without inflammatory cytokines, IL-1β and tumor necrosis factor (TNF)-α. MiR-503 expression was decreased in COPD lung fibroblasts. The expression of miR-503 was positively correlated with %FVC, %FEV1, and %DLco as well as IL-6, -8, PGE2, HGF, KGF, and VEGF in the absence or presence of IL-1ß/TNF-α. In addition, IL-8 and VEGF release from COPD lung fibroblasts were increased compared to those from control. Exogenous miR-503 inhibited VEGF release from primary adult and fetal lung fibroblasts but not IL-8 release. As expected, COPD fibroblasts proliferated more slowly than control fibroblasts. MiR-503 did not affect proliferation of either control or COPD lung fibroblasts. MiR-503 inhibition of VEGF protein production and mRNA was mediated by direct binding to the 3’ untranslated region of VEGF mRNA. Endogenous miR-503 was differently regulated by exogenous stimulants associated with COPD pathogenesis, including IL-1ß/TNF-α, TGF-ß1 and PGE2. Endogenous miR-503 inhibition augmented VEGF release by IL-1ß/TNF-α and TGF-ß1 but not by PGE2, demonstrating selectivity of miR-503 regulation of VEGF. In conclusions, reduced miR-503 augments VEGF release from lung fibroblasts from patients with COPD. Since VEGF contributes to disturbed vasculature in COPD, altered miR-503 production might play a role in modulating fibroblast-mediated vascular homeostasis in COPD.en-USMedicine and Health SciencesPulmonologyChronic Obstructive Pulmonary DiseaseBiology and Life SciencesCell BiologyCellular TypesAnimal CellsConnective Tissue CellsFibroblastsAnatomyBiological TissueConnective TissueBiology and life sciencesGeneticsGene expressionGene regulationMicroRNAsBiochemistryNucleic acidsRNANon-coding RNAOncologyCancers and NeoplasmsLung and Intrathoracic TumorsMolecular BiologyMolecular Biology TechniquesTransfectionSecondary Lung TumorsPathology and Laboratory MedicinePathogenesisEndocrinologyEndocrine PhysiologyGrowth FactorsPhysiologyJournal Article2017-12-0510.1371/journal.pone.0184039