Traditional Chinese Medicine Fuzheng Huayu Prevents Development of Liver Fibrosis in Mice

Chunyan Jiang; Keiko Iwaisako; Min Cong; Karin Diggle; Tarek Hassanein; David A Brenner; Tatiana Kisseleva

doi:10.26502/acbr.50170125

Traditional Chinese Medicine Fuzheng Huayu Prevents Development of Liver Fibrosis in Mice

Arch Clin Biomed Res. 2020;4(5):561-580. doi: 10.26502/acbr.50170125. Epub 2020 Oct 20.

Authors

Chunyan Jiang^{1

2}, Keiko Iwaisako^{3

2}, Min Cong^{1

2}, Karin Diggle², Tarek Hassanein⁴, David A Brenner², Tatiana Kisseleva⁵

Affiliations

¹ Beijing Friendship Hospital, Capital Medical University, Beijing, China.
² Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
³ Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
⁴ Southern California Liver Center, Coronado, CA, USA.
⁵ Department of Surgery, University of California, San Diego, La Jolla, CA, USA.

Abstract

Aim: To investigate the therapeutic effect of FZHY on hepatic fibrosis in mice and to determine the mechanism of its action.

Methods: Wild type mice were subjected to toxic (carbon tetrachloride, CCl₄) or cholestatic (bile duct ligation, BDL). Upon induction of liver fibrosis, mice were treated with FZHY (4.0g/kg, 2w, oral gavage) or vehicle (PBS). Livers were analyzed by Sirius Red staining, immunostaining and RT-PCR for profibrogenic and pro-inflammatory genes. The effect of FZHY on hepatocytes, inflammatory responses, activation of fibrogenic myofibroblasts, and ROS production was assessed.

Results: FZHY strongly inhibited the development of CCl₄- and BDL-induced liver fibrosis in mice. Liver fibrosis was significantly improved in FZHY-treated mice, as demonstrated by reduced content of hepatic hydroxyproline and Sirius Red positive area. Moreover, the number of SMA ⁺and Desmin⁺ myofibroblasts was significantly reduced in the livers of FZHY-treated mice, and correlated with downregulation of the mRNA levels of α-SMA, collagen-α1(I), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), TGF-β1 and its receptor TGF-βRI, and platelet-derived growth factor-β (PDGF-β), suggesting that FZHY inhibits activation of fibrogenic myofibroblasts. Furthermore, administration of FZHY markedly decreased recruitment of F4/80⁺ inflammatory macrophages to the livers of CCl₄- and BDL-injured mice, and this effect was associated with downregulation of monocyte chemoattractant protein-1(MCP-1) and macrophage inflammatory protein-1 (MIP-1) mRNA. In addition, the lipid peroxidation products 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) were reduced, demonstrating that treatment with FZHY can effectively block ROS production in livers of CCl₄- and BDL-injured mice.

Conclusions: Traditional Chinese Medicine FZHY has a variety of anti-fibrotic effects, including strong anti-oxidant, anti-inflammatory and anti-fibrotic effects on myeloid cells and hepatocytes. Although FZHY compound does not seem to directly affect HSCs, it regulates HSC activation via inhibition of macrophage recruitment to fibrotic liver.

Keywords: Fuzheng Huayu; Liver fibrosis; Reactive oxygen species; Toxic and cholestatic liver injury; Traditional Chinese medicine.

Abstract

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