Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells

• Published in: World journal of gastroenterology : WJG 2012-08, Vol.18 (31), p.4199-4206
• Main Authors: Chai, Ning-Li, Fu, Qiang, Shi, Hui, Cai, Chang-Hao, Wan, Jun, Xu, Shi-Ping, Wu, Ben-Yan
• Format: Article
• Language: English
• Subjects: Alkaline Phosphatase - metabolism; Alkaloids - administration & dosage; Alkaloids - pharmacology; Animals; Apoptosis - drug effects; Brief; Carbon Tetrachloride - adverse effects; Cell Survival - drug effects; Cells, Cultured; Disease Models, Animal; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; In Vitro Techniques; Liposomes; Liver Cirrhosis - chemically induced; Liver Cirrhosis - metabolism; Liver Cirrhosis - prevention & control; Male; Matrix Metalloproteinase 2 - metabolism; Quinolizines - administration & dosage; Quinolizines - pharmacology; Rats; Rats, Sprague-Dawley; TIMP-1; Tissue Inhibitor of Metalloproteinase-1 - metabolism; 氧化苦参碱; 肝星状细胞; 肝纤维化; 脂质体; 苦参素; 血清碱性磷酸酶; 造血干细胞
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v18.i31.4199

AIM： To investigate the potential mechanism of Arg- Gly-Asp （RGD） peptide-labeled liposome loading oxy- matrine （OM） therapy in CCI4-induced hepatic fibrosis in rats. METHODS： We constructed a rat model of CCh- induced hepatic fibrosis and treated the rats with dif- ferent formulations of OM. To evaluate the antifibrotic effect of OM, we detected levels of alkaline phospha- tase, hepatic histopathology （hematoxylin and eosin stain and Masson staining） and fibrosis-related gene expression of matrix metallopeptidase （MMP）-2, tis- sue inhibitor of metalloproteinase （TIMP）-I as well as type I procollagen via quantitative real-time poly- merase chain reaction. To detect cell viability and apop- tosis of hepatic stellate cells （HSCs）, we performed 3-（4,5）-dimethylthiahiazo（-z-yl）-3,5-diphenytetrazoli- umromide 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 CCh-induced hepatic fibro- sis, 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 en- hanced 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 en- hanced the effect of OM on HSC viability and apoptosis. CONCLUSION： OM attenuated hepatic fibrosis by in- hibiting viability and inducing apoptosis of HSCs. The RGD-labeled formulation enhanced the targeting effi- ciency for HSCs and the therapeutic effect.