Costunolide alleviated DDC induced ductular reaction and inflammatory response in murine model of cholestatic liver disease

Juan Hao; Xiaoyu Shen; Kan Lu; Yi Xu; Yiyue Chen; Jibo Liu; Xiaohong Shao; Chunling Zhu; Yaqin Ding; Xin Xie; Jian Wu; Quanjun Yang

doi:10.1016/j.jtcme.2023.02.008

Costunolide alleviated DDC induced ductular reaction and inflammatory response in murine model of cholestatic liver disease

J Tradit Complement Med. 2023 Feb 27;13(4):345-357. doi: 10.1016/j.jtcme.2023.02.008. eCollection 2023 Jul.

Authors

Juan Hao¹, Xiaoyu Shen¹, Kan Lu¹, Yi Xu¹, Yiyue Chen¹, Jibo Liu¹, Xiaohong Shao¹, Chunling Zhu¹, Yaqin Ding¹, Xin Xie¹, Jian Wu¹, Quanjun Yang²

Affiliations

¹ Department of Endocrinology, Shanghai TCM-Integrated Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Baoding 230, Hongkou, Shanghai, China.
² Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Yishan 600, Xuhui, Shanghai, 200233, China.

Abstract

Purpose: Cholestatic liver diseases are groups of hepatobiliary diseases without curative drug-based therapy options. Regulation of bile acid (BA) metabolism, hepatoperiductal fibrosis, and inflammatory response indicated present novel methods for the treatment of cholestatic liver disease. Costunolide (COS) from herb Saussurea lappa exerts a pharmacological effect of regulation of BA metabolism, liver fbrosis and inflammatory response. The present study aimed to clarify the pharmacodynamic effects of COS against the murine model of cholestatic liver disease.

Methods: We established a murine model of cholestatic liver disease through chronic feeding of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 28 days. Two independent in vivo experiments were designed to reveal the pharmacological effect of COS against cholestatic liver disease. In the first experiment, two dosages of COS (10 and 30 mg/kg) were intraperitoneally injected into model mice daily for 14 days. In the second experiment, high dosage of COS (30 mg/kg) was intraperitoneally injected into control and model mice daily for 28 days.

Results: In the evaluation of the hepatoprotective effect of COS, COS showed dosage-dependent improvement of cholestatic liver disease, including ductular reaction, hepatoperiductal fibrosis, and inflammatory response. The mechanism of COS-mediated hepatoprotective effects mainly relies on the regulation of BA metabolism, and the inflammatory response. DDC diet feed induced hepatic BA metabolism, transport and circulation dysfunction. COS treatment not only regulated the BA metabolism and transport gene, but also reprogrammed hepatic primary and secondary BA concentrations. DDC induced hepatic infiltrated monocytes derived macrophages and lymphocytes were inhibited, while Kupffer cells were preserved by COS treatment. The liver elevating inflammatory cytokines of DDC diet feed were alleviated by COS. Moreover, high dosage of 30 mg/kg COS treatment for 28 days resulted in no significant serological changes and no obvious hepatic histopathological changes when compared with control mice.

Conclusion: COS protected against DDC diet feeding-induced cholestatic liver disease since COS regulated BA metabolism, ductular reaction, hepatoperiductal fibrosis and inflammatory response. COS is suggested as a potential natural product for the treatment of cholestatic liver disease.

Keywords: Bile acid metabolism; Cholestatic liver disease; Costunolide; Ductular reaction; Inflammatory response.