Brief Article
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Aug 21, 2012; 18(31): 4199-4206
Published online Aug 21, 2012. doi: 10.3748/wjg.v18.i31.4199
Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells
Ning-Li Chai, Qiang Fu, Hui Shi, Chang-Hao Cai, Jun Wan, Shi-Ping Xu, Ben-Yan Wu
Ning-Li Chai, Hui Shi, Chang-Hao Cai, Jun Wan, Shi-Ping Xu, Ben-Yan Wu, Department of Gastroenterology, South Building of Chinese People’s Liberation Army General Hospital, Beijing 100853, China
Qiang Fu, Department of Gastroenterology, Xi’an Children’s Hospital, Xi’an 710002, Shaanxi Province, China
Author contributions: Chai NL and Fu Q performed the majority of experiments; Cai CH, Wan J and Xu SP provided vital reagents and analytical tools and were also involved in editing the manuscript; Chai NL and Wu BY designed the study; Chai NL and Shi H wrote the manuscript.
Supported by National Natural Science Foundation of China, No. 30600848
Correspondence to: Ben-Yan Wu, MD, Department of Gastroenterology, South Building of Chinese People’s Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China. csxlily@163.com
Telephone: + 86-10-66876225 Fax: +86-10-68295664
Received: May 13, 2012
Revised: June 26, 2012
Accepted: June 28, 2012
Published online: August 21, 2012
Abstract

AIM: To investigate the potential mechanism of Arg-Gly-Asp (RGD) peptide-labeled liposome loading oxymatrine (OM) therapy in CCl4-induced hepatic fibrosis in rats.

METHODS: We constructed a rat model of CCl4-induced hepatic fibrosis and treated the rats with different formulations of OM. To evaluate the antifibrotic effect of OM, we detected levels of alkaline phosphatase, hepatic histopathology (hematoxylin and eosin stain and Masson staining) and fibrosis-related gene expression of matrix metallopeptidase (MMP)-2, tissue inhibitor of metalloproteinase (TIMP)-1 as well as type I procollagen via quantitative real-time polymerase chain reaction. To detect cell viability and apoptosis of hepatic stellate cells (HSCs), we performed 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide assay and flow cytometry. To reinforce the combination of oxymatrine with HSCs, we constructed fluorescein-isothiocyanate-conjugated Arg-Gly-Asp peptide-labeled liposomes loading OM, and its targeting of HSCs was examined by fluorescent microscopy.

RESULTS: OM attenuated CCl4-induced hepatic fibrosis, as defined by reducing serum alkaline phosphatase (344.47 ± 27.52 U/L vs 550.69 ± 43.78 U/L, P < 0.05), attenuating liver injury and improving collagen deposits (2.36% ± 0.09% vs 7.70% ± 0.60%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). OM inhibited cell viability and induced apoptosis of HSCs in vitro. RGD promoted OM targeting of HSCs and enhanced the therapeutic effect of OM in terms of serum alkaline phosphatase (272.51 ± 19.55 U/L vs 344.47 ± 27.52 U/L, P < 0.05), liver injury, collagen deposits (0.26% ± 0.09% vs 2.36% ± 0.09%, P < 0.05) and downregulating fibrosis-related gene expression, that is, MMP-2, TIMP-1 and type I procollagen (P < 0.05). Moreover, in vitro assay demonstrated that RGD enhanced the effect of OM on HSC viability and apoptosis.

CONCLUSION: OM attenuated hepatic fibrosis by inhibiting viability and inducing apoptosis of HSCs. The RGD-labeled formulation enhanced the targeting efficiency for HSCs and the therapeutic effect.

Keywords: Oxymatrine, Arg-Gly-Asp peptide, Hepatic stellate cell, Hepatic fibrosis, Target therapy