Abstract
Liver fibrosis is characterized by activated hepatic stellate cells (HSC) and extracellular matrix accumulation. Blocking the activation of HSC and the inflammation response are two major effective therapeutic strategies for liver fibrosis. In addition to the long history of using andrographolide (Andro) for inflammatory disorders, we aimed at elucidating the pharmacological effects and potential mechanism of Andro on liver fibrosis. In this study, liver fibrosis was induced by carbon tetrachloride (CCl4) and the mice were intraperitoneally injected with Andro for 6 weeks. HSC cell line (LX-2) and primary HSC were also treated with Andro in vitro. Treatment of CCl4-induced mice with Andro decreased the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), Sirius red staining as well as the expression of α smooth muscle actin (α-SMA) and transforming growth factor- (TGF-) β1. Furthermore, the expression of Toll-like receptor (TLR)4 and NF-κB p50 was also inhibited by Andro. Additionally, in vitro data confirmed that Andro treatment not only attenuated the expression of profibrotic and proinflammatory factors but also blocked the TGF-β1/Smad2 and TLR4/NF-κB p50 pathways. These results demonstrate that Andro prevents liver inflammation and fibrosis, which is in correlation with the inhibition of the TGF-β1/Smad2 and TLR4/NF-κB p50 pathways, highlighting Andro as a potential therapeutic strategy for liver fibrosis.
Highlights
Liver fibrosis is a reversible wound healing response which results from chronic liver injury in various chronic hepatic diseases, including hepatitis B and C, alcoholic liver disease, and nonalcoholic steatohepatitis [1, 2]
These results demonstrate that Andro prevents liver inflammation and fibrosis, which is in correlation with the inhibition of the transforming growth factor- (TGF-)β1/Smad2 and Toll-like receptor-4 nuclear factor κB (NF-κB) (TLR4)/NF-κB p50 pathways, highlighting Andro as a potential therapeutic strategy for liver fibrosis
Strategies aiming at inhibiting TLR4 signaling pathways have displayed a profound reduction in hepatic fibrogenesis [13]. These results demonstrated the causal roles of TLR4 and transforming growth factor-β1 (TGF-β1) signaling in regulating hepatic stellate cells (HSC) activation and promoting the progression of liver fibrosis
Summary
Liver fibrosis is a reversible wound healing response which results from chronic liver injury in various chronic hepatic diseases, including hepatitis B and C, alcoholic liver disease, and nonalcoholic steatohepatitis [1, 2]. Upon the activation of hepatic stellate cells (HSC) by various stimuli, such as transforming growth factor- (TGF-) β, quiescent HSC transdifferentiate into myofibroblasts and play a key role in the pathogenesis of hepatic fibrosis by producing extracellular matrix (ECM) proteins [4]. The transforming growth factor-β1 (TGF-β1) has been well demonstrated to be the key cytokine during fibrogenesis. It plays a vital role in transforming quiescent HSC into fibrogenic myofibroblasts by stimulating the synthesis of ECM as well as inhibiting their degradation [5]. TLR4 expressed on activated HSC enhanced TGF-β1-mediated HSC activation and ECM production [9]. TLRs belong to a highly conserved family of receptors that recognize
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