Abstract
Activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrogenesis. armepavine (Arm, C19H23O3N), an active compound from Nelumbo nucifera, has been shown to exert immunosuppressive effects on T lymphocytes and on lupus nephritic mice. The aim of this study was to investigate whether Arm could exert anti-hepatic fibrogenic effects in vitro and in vivo. A cell line of rat HSCs (HSC-T6) was stimulated with tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS) to evaluate the inhibitory effects of Arm. An in vivo therapeutic study was conducted in bile duct-ligated (BDL) rats. BDL rats were given Arm (3 or 10 mg/kg) by gavage twice daily for 3 weeks starting from the onset of BDL. Liver sections were taken for fibrosis scoring, immuno-fluorescence staining and quantitative real-time mRNA measurements. In vitro, Arm (1-10 μM) concentration-dependently attenuated TNF-α- and LPS-stimulated α-SMA protein expression and AP-1 activation by HSC-T6 cells without adverse cytotoxicity. Arm also suppressed TNF-α-induced collagen collagen deposition, NFκB activation and MAPK (p38, ERK1/2, and JNK) phosphorylations. In vivo, Arm treatment significantly reduced plasma AST and ALT levels, hepatic α-SMA expression and collagen contents, and fibrosis scores of BDL rats as compared with vehicle treatment. Moreover, Arm attenuated the mRNA expression levels of col 1α2, TGF-β1, TIMP-1, ICAM-1, iNOS, and IL-6 genes, but up-regulated metallothionein genes. Our study results showed that Arm exerted both in vitro and in vivo antifibrotic effects in rats, possibly through anti-NF-κB activation pathways.
Highlights
Liver fibrosis is a wound-healing response to various chronic liver injuries, including alcoholism, persistent viral and helminthic infections, and hereditary metal overload [1,2]
In vitro effects of Arm on hepatic stellate cell (HSC)-T6 cells Effects of Arm on tumor necrosis factor-α (TNF-α)-induced collagen deposition in HSCs As shown in Figure 1a, TNF-α (10 ng/ml) stimulated collagen deposition in HSC-T6 cells to 143 ± 9% of the unstimulated, control level, which was concentrationdependently reduced by Arm (1 - 10 μM)
We observed in vitro that Arm exerted in HSC-T6 cells several inhibitory effects, including (a) attenuation of TNF-α-induced collagen deposition and αSMA protein expression, (b) inhibition of TNF-α-induced nuclear factor-κB (NFκB) and activating protein-1 (AP-1) activities, together with IκBα phosphorylation and NFκB p65 nuclear translocation, (c) downregulation of mRNA expressions of inducible nitric oxide synthase (iNOS), collagen 1α2, tissue inhibitor of metalloproteinase-1 (TIMP-1) and α-smooth muscle actin (α-SMA) genes, (d) attenuation of LPS-induced α-SMA protein expression and AP-1 activities, (e) suppression of TNF-α-induced Mitogen-activated protein kinases (MAPKs) (p38, ERK1/2, and jun N-terminal kinas (JNK)) phosphorylations
Summary
Liver fibrosis is a wound-healing response to various chronic liver injuries, including alcoholism, persistent viral and helminthic infections, and hereditary metal overload [1,2]. Activation of hepatic stellate cells (HSCs) plays a crucial role in the development of liver fibrosis [15]. Activated HSCs are proliferative and fibrogenic, with accumulation of extracellular matrix (ECM), including type I collagen. Prolonged liver injury and inflammation result in hepatocyte damage, which triggers activation of HSCs and recruitment of inflammatory cells such as macrophages. Journal of Biomedical Science 2009, 16:78 http://www.jbiomedsci.com/content/16/1/78 into the liver by paracrine secretion of cytokines [1,2]. Activated HSCs have been implicated in hepatic inflammation through their ability to secrete cytokines and chemokines, and express adhesion molecules [1,2,3,4]
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