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Downregulation of microRNA-9 reduces inflammatory response and fibroblast proliferation in mice with idiopathic pulmonary fibrosis through the ANO1-mediated TGF-β-Smad3 pathway.

著者 Dai WJ , Qiu J , Sun J , Ma CL , Huang N , Jiang Y , Zeng J , Ren BC , Li WC , Li YH
J Cell Physiol.2018 Aug 24 ; ():.
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Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with increasing occurrence, high death rates and unfavorable treatment regimens. In the current study, we identified the expression of microRNA-9 (miR-9) and anoctamin-1 (ANO1) in IPF mouse models induced by bleomycin, and their effects on inflammation and fibroblast proliferation through the transforming growth factor-β (TGF-β)-Smad3 pathway. To verify the targeting relationship between miR-9 and ANO1, we used bioinformatics prediction and conducted a dual-luciferase reporter gene assay. The underlying regulatory mechanisms of miR-9 and the target gene ANO1 were investigated mainly with the treatment of miR-9 mimic, miR-9 inhibitor, or siRNA against ANO1 in fibroblasts isolated from IPF mice. Enzyme-linked immunosorbent assay was performed to investigate the effect of miR-9 or ANO1 on inflammatory factors. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry were used to detect fibroblast proliferation and apoptosis. Reverse transcription quantitative polymerase chain reaction and western blot analysis were applied to measure the expression of the TGF-β-Smad3 pathway-related genes. The determination of luciferase activity suggested that miR-9 targets ANO1. Upregulation of miR-9 or silencing of ANO1 intensified inflammation in IPF, promoted proliferation and inhibited apoptotic ability of lung fibroblasts. MiR-9 negatively modulated ANO1, and thus activated the TGF-β-Smad3 pathway. These findings suggest that miR-9 can indirectly activate the TGF-β-Smad3 pathway by inhibiting the expression of ANO1, thereby aggravating inflammation, promotes proliferation and suppressing apoptosis of lung fibroblasts in mice models of IPF.
PMID: 30144053 [PubMed - as supplied by publisher]
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