Abstract
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-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3′ UTR region of transforming growth factor β receptor II (TGF-βRII) mRNA, and this is associated with reduced TGF-βRII expression and suppression of TGF-β-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-βRII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of IPF.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 728-738 |
| Number of pages | 11 |
| Journal | Molecular Therapy |
| Volume | 25 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2017 |
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Keywords
- TGF-β1
- epithelial-mesenchymal transition
- fibrosis
- miR-18a
- pleural mesothelial cells
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery
Cite this
miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-β Receptor II. / Zhang, Qian; Ye, Hong; Xiang, Fei; Song, Lin Jie; Zhou, Li Ling; Cai, Peng Cheng; Zhang, Jian Chu; Yu, Fan; Shi, Huan Zhong; Su, Yunchao; Xin, Jian Bao; Ma, Wan Li.
In: Molecular Therapy, Vol. 25, No. 3, 01.03.2017, p. 728-738.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-β Receptor II
AU - Zhang, Qian
AU - Ye, Hong
AU - Xiang, Fei
AU - Song, Lin Jie
AU - Zhou, Li Ling
AU - Cai, Peng Cheng
AU - Zhang, Jian Chu
AU - Yu, Fan
AU - Shi, Huan Zhong
AU - Su, Yunchao
AU - Xin, Jian Bao
AU - Ma, Wan Li
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3′ UTR region of transforming growth factor β receptor II (TGF-βRII) mRNA, and this is associated with reduced TGF-βRII expression and suppression of TGF-β-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-βRII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of IPF.
AB - 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-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3′ UTR region of transforming growth factor β receptor II (TGF-βRII) mRNA, and this is associated with reduced TGF-βRII expression and suppression of TGF-β-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-βRII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of IPF.
KW - TGF-β1
KW - epithelial-mesenchymal transition
KW - fibrosis
KW - miR-18a
KW - pleural mesothelial cells
UR - http://www.scopus.com/inward/record.url?scp=85016275490&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016275490&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2016.12.017
DO - 10.1016/j.ymthe.2016.12.017
M3 - Article
VL - 25
SP - 728
EP - 738
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 3
ER -