title: Oxymatrine attenuates CCl4-induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF-β1 signaling pathways.
abstract: Oxymatrine (OMT) is able to effectively protect against hepatic fibrosis because of its anti-inflammatory property, while the underlying mechanism remains incompletely understood. In this study, forty rats were randomly divided into five groups: control group, model group (carbon tetrachloride, CCl4) and three OMT treatment groups (30, 60, 120mg/kg). After CCl4 alone, the fibrosis score was 20.2±0.8, and the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hydroxyproline content, and collagen I expression was elevated, but OMT blunted these parameters. Treatment with OMT prevented CCl4-induced increases in expression of pro-inflammatory and pro-fibrotic cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α, meanwhile OMT promoted the expression of anti-inflammatory and anti-fibrotic factors such as interleukin (IL)-10 and bone morphogenetic protein and activin membrane-bound inhibitor (Bambi). Moreover, lipopolysaccharides (LPS) and high mobility group box-1 (HMGB1), which activates Toll-like receptor 4 (TLR4) and modulate hepatic fibrogenesis through hepatic stellate cells (HSCs) or Kupffer cells, were significantly decreased by OMT treatment. These results were further supported by in vitro data. First, OMT suppressed the expression of TLR4 and its downstream pro-inflammatory cytokines, lowered the level of HMGB1, TGF-β1 in macrophages. Then, OMT promoted Bambi expression and thereby inhibited activation of HSCs mediated by transforming growth factor (TGF)-β1. In conclusion, this study showed that OMT could effectively attenuate the CCl4-induced hepatic fibrosis, and this effect may be due to modulation of TLR4-dependent inflammatory and TGF-β1 signaling pathways.
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; Jiangxi University of Traditional Chinese Medicine, Jiangxi 330004, China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Zhao
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; Chengde Medical College, Hebei 067000, China.
authors.forename: Zhen-Fang
authors.initials: ZF
authors.lastname: Zhang
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Chai
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 610000, China.
authors.forename: Guang-Quan
authors.initials: GQ
authors.lastname: Li
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; Chengde Medical College, Hebei 067000, China.
authors.forename: He-Rong
authors.initials: HR
authors.lastname: Cui
authors.affiliation: Department of Hepatobiliary Surgery Center, 302 Military Hospital, Beijing 100039, China.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Wang
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; Jiangxi University of Traditional Chinese Medicine, Jiangxi 330004, China.
authors.forename: Ya-Kun
authors.initials: YK
authors.lastname: Meng
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; Chengde Medical College, Hebei 067000, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Liu
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China.
authors.forename: Jia-Bo
authors.initials: JB
authors.lastname: Wang
authors.affiliation: Animral Laboratory Center, 302 Hospital of PLA, Beijing 100039, China.
authors.forename: Rui-Sheng
authors.initials: RS
authors.lastname: Li
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China. Electronic address: baizf2008@hotmail.com.
authors.forename: Zhao-Fang
authors.initials: ZF
authors.lastname: Bai
authors.affiliation: Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China. Electronic address: pharmacy302@163.com.
authors.forename: Xiao-He
authors.initials: XH
authors.lastname: Xiao
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000470:Alkaloids / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002251:Carbon Tetrachloride / Q000633:toxicity; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011807:Quinolizines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000093842:Matrines
chemical_list: D000410:Alanine Transaminase; D000470:Alkaloids; D000893:Anti-Inflammatory Agents; D002251:Carbon Tetrachloride; D016207:Cytokines; D008565:Membrane Proteins; D011807:Quinolizines; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; C485672:Bambi protein, mouse; C495347:Tlr4 protein, rat; C037573:oxymatrine; D000093842:Matrines
keywords: Bambi; HMGB1; Hepatic fibrosis; Oxymatrine; Toll like receptor 4