title: miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-β Receptor II.
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.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei 430030, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei 430030, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xiang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Lin-Jie
authors.initials: LJ
authors.lastname: Song
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Li-Ling
authors.initials: LL
authors.lastname: Zhou
authors.affiliation: Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
authors.forename: Peng-Cheng
authors.initials: PC
authors.lastname: Cai
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei 430030, China.
authors.forename: Jian-Chu
authors.initials: JC
authors.lastname: Zhang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei 430030, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
authors.forename: Huan-Zhong
authors.initials: HZ
authors.lastname: Shi
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
authors.forename: Yunchao
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei 430030, China. Electronic address: 814643835@qq.com.
authors.forename: Jian-Bao
authors.initials: JB
authors.lastname: Xin
authors.affiliation: Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei 430030, China. Electronic address: whmawl@aliyun.com.
authors.forename: Wan-Li
authors.initials: WL
authors.lastname: Ma
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D002415:Cats; D002465:Cell Movement / Q000235:genetics; D016000:Cluster Analysis; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010994:Pleura / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D001761:Bleomycin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: TGF-β1; epithelial-mesenchymal transition; fibrosis; miR-18a; pleural mesothelial cells