Lipopolysaccharide modification enhances the inhibitory effect of clodronate liposomes on hepatic fibrosis by depletion of macrophages and hepatic stellate cells

Luyao Zhang; Min Tao; Hengyan Zhang; Shichao Zhang; Xiaojuan Hou; Chen Zong; Gangqi Sun; Shiyao Feng; Haixin Yan; Ying Lu; Xue Yang; Lixin Wei; Li Zhang

doi:10.1016/j.cbi.2024.111015

Lipopolysaccharide modification enhances the inhibitory effect of clodronate liposomes on hepatic fibrosis by depletion of macrophages and hepatic stellate cells

Chem Biol Interact. 2024 Apr 23:395:111015. doi: 10.1016/j.cbi.2024.111015. Online ahead of print.

Authors

Luyao Zhang¹, Min Tao¹, Hengyan Zhang², Shichao Zhang³, Xiaojuan Hou⁴, Chen Zong⁴, Gangqi Sun⁵, Shiyao Feng⁶, Haixin Yan⁶, Ying Lu⁷, Xue Yang⁸, Lixin Wei⁹, Li Zhang¹⁰

Affiliations

¹ School of Pharmacy, Anhui Medical University, Hefei, China; Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China; Clinical Research Unit, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
² Clinical Research Unit, The First Affiliated Hospital of Naval Medical University, Shanghai, China.
³ Department of Hepatic Surgery, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
⁴ The National Center for Liver Cancer, Shanghai, China; Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China.
⁵ Molecular Pathology Center, Zhongshan Hospital, Fudan University, Shanghai, China.
⁶ Department of Urology, Second Affiliated Hospital, Anhui Medical University, Hefei, China.
⁷ Department of Pharmaceutical Sciences, School of Pharmacy, Naval Medical University, Shanghai, China.
⁸ The National Center for Liver Cancer, Shanghai, China; Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China. Electronic address: yangxue19900307@126.com.
⁹ The National Center for Liver Cancer, Shanghai, China; Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China. Electronic address: weilixin_smmu@163.com.
¹⁰ School of Pharmacy, Anhui Medical University, Hefei, China; Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China; Clinical Research Unit, The First Affiliated Hospital of Naval Medical University, Shanghai, China. Electronic address: lizhangpaper@163.com.

PMID: 38663797
DOI: 10.1016/j.cbi.2024.111015

Abstract

Hepatic fibrosis is a complex chronic liver disease in which both macrophages and hepatic stellate cells (HSCs) play important roles. Many studies have shown that clodronate liposomes (CLD-lipos) effectively deplete macrophages. However, no liposomes have been developed that target both HSCs and macrophages. This study aimed to evaluate the therapeutic efficacy of lipopolysaccharide-coupled clodronate liposomes (LPS-CLD-lipos) and the effects of liposomes size on hepatic fibrosis. Three rat models of hepatic fibrosis were established in vivo; diethylnitrosamine (DEN), bile duct ligation (BDL), and carbon tetrachloride (CCl₄). Hematoxylin and eosin staining and serological liver function indices were used to analyze pathological liver damage. Masson's trichrome and Sirius red staining were used to evaluate the effect of liposomes on liver collagen fibers. The hydroxyproline content in liver tissues was determined. In vitro cell counting kit-8 (CCK-8) and immunofluorescence assays were used to further explore the effects of LPS modification and liposomes size on the killing of macrophages and HSCs. Both in vitro and in vivo experiments showed that 200 nm LPS-CLD-lipos significantly inhibited hepatic fibrosis and the abnormal deposition of collagen fibers in the liver and improved the related indicators of liver function. Further results showed that 200 nm LPS-CLD-lipos increased the clearance of macrophages and induced apoptosis of hepatic stellate cells, significantly. The present study demonstrated that 200 nm LPS-CLD-lipos could significantly inhibit hepatic fibrosis and improve liver function-related indices and this study may provide novel ideas and directions for hepatic fibrosis treatment.

Keywords: Active hepatic stellate cells; Clodronate liposomes; Hepatic fibrosis; Lipopolysaccharide; Macrophages.