title: Arsenic trioxide prevents rat pulmonary fibrosis via miR-98 overexpression.
abstract: OBJECTIVE
  This study aimed to investigate the pathogenesis mechanisms of bleomycin (BLM)-induced pulmonary fibrosis (PF) in Sprague-Dawley rats and explore the anti-fibrotic role of arsenic trioxide (As2O3) in preventing PF.
  
  
  METHODS
  Intratracheal instillation of BLM was performed to establish PF rat models. The treatment group was treated with As2O3 (0.4 mg/kg/day). Morphological changes were observed by hematoxylin-eosin and Masson staining. Related proteins were determined by immunohistochemistry, immunofluorescence, and Western blot. MicroRNA detection was performed by quantitative real-time polymerase chain reaction.
  
  
  RESULTS
  As a novel miRNA in PF, miR-98 decreased in the fibrotic lung tissues. Based on microRNA analysis software, we found that Stat3-3'-UTR is targeted by miR-98. Then, we found that Stat3 was activated with PF development and the expression of Stat3 and p-Stat3 was significantly increased in BLM-induced PF at day 28 compared with saline-treated rats. Our results showed that both Stat3 and p-Stat3 were significantly decreased in miR-98-treated A549 cells compared with that in mu-98-treated cultures or untreated controls. The fibrotic marker α-SMA was upregulated, whereas E-cadherin was inhibited in fibrotic lung tissues. The ratio of apoptotic factors Bax/Bcl-2 increased with the development of fibrosis. Furthermore, As2O3 treatment prevented lung interstitial thickening and inhibited the collagen type I and hydroxyproline, thereby preventing the development of PF. As2O3 also significantly down-regulated α-SMA but increased E-cadherin and miR-98 levels.
  
  
  CONCLUSIONS
  The study revealed that arsenic trioxide prevented rat PF by up-regulation of miR-98 and inhibition of its downstream Stat3 signals.
authors.affiliation: Department of Clinical Medicine, Binzhou Medical University, Yantai 264003, China; Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, China.
authors.forename: Shu-Yan
authors.initials: SY
authors.lastname: Gao
authors.affiliation: Department of Clinical Medicine, Binzhou Medical University, Yantai 264003, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, China.
authors.forename: You-Jie
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Clinical Medicine, Binzhou Medical University, Yantai 264003, China.
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Liu
authors.affiliation: Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, China.
authors.forename: Ping-Yu
authors.initials: PY
authors.lastname: Wang
authors.affiliation: Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, China.
authors.forename: Min
authors.initials: M
authors.lastname: Pang
authors.affiliation: Department of Clinical Medicine, Binzhou Medical University, Yantai 264003, China; Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, China. Electronic address: shuyangxie@aliyun.com.
authors.forename: Shu-Yang
authors.initials: SY
authors.lastname: Xie
authors.affiliation: Department of Clinical Medicine, Binzhou Medical University, Yantai 264003, China. Electronic address: changjun_lv@163.com.
authors.forename: Chang-Jun
authors.initials: CJ
authors.lastname: Lv
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001761:Bleomycin / Q000633:toxicity*; D015820:Cadherins / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006909:Hydroxyproline / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D010087:Oxides / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000199:Actins; D000077237:Arsenic Trioxide; D001152:Arsenicals; D001761:Bleomycin; D015820:Cadherins; D024042:Collagen Type I; D006909:Hydroxyproline; D035683:MicroRNAs; D010087:Oxides; D050796:STAT3 Transcription Factor; C571630:MIRN98 microRNA-98, rat; C498862:Acta2 protein, rat
keywords: As(2)O(3); Gene expression; Pulmonary fibrosis; Stat3 signals; miR-98