TY -的T1 - mir - 184 hyperoxia-induced提供中介injury by targeting cell death and angiogenesis signalling pathways in the developing lung JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.01789-2019 SP - 1901789 AU - Shah, Dilip AU - Sandhu, Karmyodh AU - Das, Pragnya AU - Aghai, Zubair H. AU - Andersson, Sture AU - Pryhuber, Gloria AU - Bhandari, Vineet Y1 - 2020/01/01 UR - //www.qdcxjkg.com/content/early/2020/07/30/13993003.01789-2019.abstract N2 - MicroRNAs (miRs) have been shown to disrupt normal lung development and function by interrupting alveolarization and vascularisation leading to development of bronchopulmonary dysplasia (BPD). Here we report that miR-184 has a critical role in the induction of BPD phenotype characterised by abnormal alveolarization and pulmonary angiogenesis in the developing lung. We observed an increased expression of miR-184 in BPD clinical specimens: tracheal aspirates (TA), human neonatal lungs with BPD and in fetal human lung Type II alveolar epithelial cells (TIIAECs) exposed to hyperoxia. Consistent with this, we also detected an upregulated miR-184-3p expression in whole lungs, in freshly isolated TIIAECs from lungs of hyperoxia-induced experimental BPD mice and in fetal mice lung TIIAECs exposed to hyperoxia. We demonstrate that overexpression of miR-184-3p exacerbates the BPD pulmonary phenotype, while downregulation of miR-184-3p expression ameliorated the BPD phenotype and also improved respiratory function. We identified miR-184 specific targets: platelet-derived growth factor-beta (Pdgf-β) and friend of Gata 2 (Fog2), also known as zinc finger protein family member (Zfpm2), and show that they are critically involved in pulmonary alveolarization and angiogenesis. Using cell-based luciferase analysis, downregulation of miR-184-3p expression and gene knockdown of miR-184-3p targets Pdgf-β and Fog2 in lung TIIAECs and endothelial cells, we mechanistically show that inhibition of miR-184-3p expression improves pulmonary alveolarization by regulating PDGF-β/AKT/Foxo3/Bax, Bcl2 signalling and enhances angiogenesis by Fog2/VEGF-A/Angiopoietin-1/2 pathway. Collectively, these data suggest that the use of miR-184-3p specific inhibitors may act as novel therapeutic interventions to control the adverse effects of hyperoxia on lung development and function.FootnotesSince the online publication of this early view article on 26 May 2020, the editors have been made aware of potential issues with some of the images used. This note has been added to make readers aware that this issue is currently being investigated by the editors and the authors. This note will be removed and a correction published, if found necessary by the investigation. The article was updated with this note and republished on 4 August, 2020.This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Shah has nothing to disclose.Conflict of interest: Dr. Sandhu has nothing to disclose.Conflict of interest: Dr. Das has nothing to disclose.Conflict of interest: Dr. Aghai has nothing to disclose.Conflict of interest: Dr. Andersson has nothing to disclose.Conflict of interest: Dr. Pryhuber has nothing to disclose.Conflict of interest: Dr. Bhandari has nothing to disclose. ER -