Oxymatrine attenuates CCl sub(4)-induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF- beta 1 signaling pathways

• Published in: International immunopharmacology 2016-07, Vol.36, p.249-255
• Main Authors: Zhaoa, Hong-wei, Zhanga, Zhen-fang, Chaia, Xuan, Lia, Guang-quan, Cuia, He-rong, Wangf, Hong-bo, Menga, Ya-kun, Liua, Hui-min, Wanga, Jia-bo, Lig, Rui-sheng, Baia, Zhao-fang, Xiaoa, Xiao-he
• Format: Article
• Language: English
• ISSN: 1567-5769
• DOI: 10.1016/j.intimp.2016.04.040

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, CCl sub(4)) and three OMT treatment groups (30, 60, 120 mg/kg). After CCl sub(4) alone, the fibrosis score was 20.2 plus or minus 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 CCl sub(4)-induced increases in expression of pro-inflammatory and pro-fibrotic cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)- alpha , 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- beta 1 in macrophages. Then, OMT promoted Bambi expression and thereby inhibited activation of HSCs mediated by transforming growth factor (TGF)- beta 1. In conclusion, this study showed that OMT could effectively attenuate the CCl sub(4)-induced hepatic fibrosis, and this effect may be due to modulation of TLR4-dependent inflammatory and TGF- beta 1 signaling pathways.