Journal
MOLECULAR THERAPY
Volume 25, Issue 3, Pages 728-738Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2016.12.017
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Funding
- National Natural Science Foundation of China [81300047, 81370186, 81573485, 91643101, 31271490, 81570087, 81200020, 81470257]
- National Science and Technology Program of Social Development, Ministry of Science and Technology of China [2012BA105B02]
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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease that typically leads to respiratory failure and death within 3-5 years of diagnosis. Sub-pleural pulmonary fibrosis is a pathological hallmark of IPF. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition (EMT) contributes to pleural mesothelial cell (PMC) migration and sub-pleural pulmonary fibrosis. MicroRNA (miRNA) expression has recently been implicated in the pathogenesis of IPF. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3' UTR region of transforming growth factor beta receptor II (TGF-ORII) mRNA, and this is associated with reduced TGF-ORII expression and suppression of TGF-beta-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-pleural pulmonary fibrosis through upregulation of its target, TGF-beta RII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of IPF.
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