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Int Immunopharmacol. 2016 Jul;36:249-255. doi: 10.1016/j.intimp.2016.04.040. Epub 2016 May 11.

Oxymatrine attenuates CCl4-induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF-β1 signaling pathways.

Author information

1
Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; Jiangxi University of Traditional Chinese Medicine, Jiangxi 330004, China.
2
Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; Chengde Medical College, Hebei 067000, China.
3
Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; Academy of Military Medical Sciences, Beijing 100850, China.
4
Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 610000, China.
5
Department of Hepatobiliary Surgery Center, 302 Military Hospital, Beijing 100039, China.
6
Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China.
7
Animral Laboratory Center, 302 Hospital of PLA, Beijing 100039, China.
8
Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China. Electronic address: baizf2008@hotmail.com.
9
Department of Integrative Medical Center, 302 Military Hospital, Beijing 100039, China. Electronic address: pharmacy302@163.com.

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.

KEYWORDS:

Bambi; HMGB1; Hepatic fibrosis; Oxymatrine; Toll like receptor 4

PMID:
27179304
DOI:
10.1016/j.intimp.2016.04.040
[Indexed for MEDLINE]

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