Effects of a New Bioactive Lipid-Based Drug Carrier on Cultured Hepatic Stellate Cells and Liver Fibrosis in Bile Duct-Ligated Rats

Adrian, Joanna E.; Poelstra, Klaas; Scherphof, Gerrit L.; Meijer, Dirk K. F.; Loenen-Weemaes, Anne-miek van; Reker‐Smit, Catharina; Morselt, Henriëtte W. M.; Zwiers, Peter J.; Kamps, Jan A. A. M.

doi:10.1124/jpet.106.117945

Cited by 43 publications

(19 citation statements)

References 38 publications

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“…Hepatic fibrosis, which may lead to cirrhosis, is associated with most chronic liver diseases [22] . Hepatic fibrosis is thought to be a reversible disease, however, there is no satisfactory method in clinical practice to reverse the pathological process yet [23] . Several drugs, including antisense TGF-β1 receptors, cytokines [24] , antioxidants, chemical drugs [25] , soluble type Ⅱ receptor of TGF-β1, and TGF-β1 antibodies [26] have been used in research work to block experimental hepatic fibrosis, but their effects were not as prosperous as we had expected.…”

Section: Discussionmentioning

confidence: 99%

Emodin protects rat liver from CCl₄-induced fibrogenesis via inhibition of hepatic stellate cells activation

Dong¹,

Yan²,

Zhang³

et al. 2009

WJG

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AIM: To investigate the role of emodin in protecting the liver against fibrogenesis caused by carbon tetrachloride (CCl4) in rats and to further explore the underlying mechanisms. METHODS:Rat models of experimental hepatic fibrosis were established by injection with CCl4; the treated rats received emodin via oral administration at a dosage of 20 mg/kg twice a week at the same time. Rats injected with olive oil served as a normal group. Histopathological changes were observed by hematoxylin and eosin staining. The activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and hepatic hydroxyproline content were assayed by biochemical analyses. The mRNA and protein relevant to hepatic stellate cell (HSC) activation in the liver were assessed using real-time reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, western blotting and enzymelinked immunosorbent assay. RESULTS:The degree of hepatic fibrosis increased markedly in the CCl4 group compared to the normal group (P < 0.01), and decreased markedly in the emodin group compared to the CCl4 group according to METAVIR scale (P < 0.01) compared with those in the normal control group (51.02 ± 10.64 IU/L and 132.28 ± 18.14 IU/L). The activities of serum ALT and AST were significantly higher in rats injected with CCl4 (289.25 ± 68.84 IU/L and 423.89 ± 35.67 IU/L, both P < 0.05).The activities of serum ALT and AST were significantly reduced by administration of emodin (176.34 ± 4 7. 2 9 I U / L a n d 2 2 6 . 1 ± 4 4. 5 2 I U / L , b o t h P < 0.05). Compared with the normal controls (54.53 ± 13.46 mg/g), hepatic hydroxyproline content was significantly higher in rats injected with CCl4 (120.27 ± 28.47 mg/g, P < 0.05). Hepatic hydroxyproline content was significantly reduced in the rats treated with emodin at 20 mg/kg (71.25 ± 17.02 mg/g, P < 0.05).Emodin significantly protected the liver from injury by reducing serum AST and ALT activities and reducing hepatic hydroxyproline content. The mRNA levels of transforming growth factor-β1 (TGF-β1), Smad4 and α-SMA in liver tissues were significantly down-regulated in SD rats that received emodin treatment. Furthermore, significant down-regulation of serum TGF-β1 protein levels and protein expression of Smad4 and α-SMA in liver tissues was also observed in the rats. Emodin inhibited HSC activation by reducing the abundance of TGF-β1 and Smad4. CONCLUSION:Emodin protects the rat liver from CCl4-induced fibrogenesis by inhibiting HSC activation. Emodin might be a therapeutic antifibrotic agent for the treatment of hepatic fibrosis.

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Section: Discussionmentioning

confidence: 99%

Emodin protects rat liver from CCl₄-induced fibrogenesis via inhibition of hepatic stellate cells activation

Dong¹,

Yan²,

Zhang³

et al. 2009

WJG

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“…Further improvements in the targeting effects of antifibrotic drugs might be achieved by coupling ligands selective for the target cells to the liposome surface. However, a previously confirmed targeting approach, incorporation of M6P-HSA-modified human albumin into liposomes, did not show any improvement in anti-inflammatory and antifibrotic effects of bioactive lipid dilinoleoylphosphatidylcholine (DLPC) in a BDL model of rat hepatic fibrosis, and the inflammatory responses were even worse in animals receiving M6P-HSA-liposomes containing DLPC than in those receiving DLPC-liposomes without M6P-HSA incorporation (Adrian et al, 2007). We are not clear why the conflicting results were obtained.…”

Section: Targeting Drug Delivery To Hepatic Stellate Cells 565mentioning

confidence: 99%

Cyclic Arg-Gly-Asp Peptide-Labeled Liposomes for Targeting Drug Therapy of Hepatic Fibrosis in Rats

Du¹,

Pan²,

Lü³

et al. 2007

J Pharmacol Exp Ther

104

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Targeting hepatic stellate cells (HSCs) has been challenging due to the lack of specific receptors or motifs on the cells. The aim of the present study was to develop a HSC-specific system for improving drug delivery to HSCs. The affinity of a cyclic peptide containing Arg-Gly-Asp (cRGD) to collagen type VI receptor on HSCs was examined in both in vitro and in vivo experiments. Sterically stable liposomes (SSLs) were modified with this peptide to yield a new carrier, cRGD-SSL. The targeting efficiency of this carrier in delivering interferon (IFN)-␣1b was investigated in a rat model of liver fibrosis induced by bile duct ligation (BDL). When incubating HSCs or hepatocytes with cyclic RGD peptide, the peptide was bound preferentially to activated HSCs. Biodistribution study showed that the accumulation of cRGD peptide-labeled liposomes in HSCs isolated from BDL rats was 10-fold more than unlabeled SSLs. BDL rats receiving injections of IFN-␣1b entrapped in cRGD-SSL exhibited significantly reduced extent of liver fibrosis compared with BDL control rats or BDL rats treated with IFN-␣1b entrapped in SSLs. Thus, cRGD-SSL is an efficient drug carrier, which selectively targets activated HSCs and improves drug therapy for liver fibrosis to a significant extent. This liposomal formulation represents a new means of targeting drug carrier for the treatment of liver fibrosis, and it may have potential clinical applications.

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“…Previous therapies have targeted HSCs to block their fibrogenic functions, such as matrix production (Adrian et al, 2007;Sato et al, 2008;Son et al, 2009); but we have targeted HSCs to induce the production of HGF and hepatic regeneration. Our approach targeted HGF to the fibrotic foci, where regenerative capacity could be lacking.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis

et al. 2013

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Liver fibrosis generates fibrotic foci with abundant activated hepatic stellate cells and excessive collagen deposition juxtaposed with healthy regions. Targeted delivery of antifibrotic therapeutics to hepatic stellate cells (HSCs) might improve treatment outcomes and reduce adverse effects on healthy tissue. We delivered the hepatocyte growth factor (HGF) gene specifically to activated hepatic stellate cells in fibrotic liver using vitamin A-coupled liposomes by retrograde intrabiliary infusion to bypass capillarized hepatic sinusoids. The antifibrotic effects of DsRed2-HGF vector encapsulated within vitamin A-coupled liposomes were validated by decreases in fibrotic markers in vitro. Fibrotic cultures transfected with the targeted transgene showed a significant decrease in fibrotic markers such as transforming growth factor-b1. In rats, dimethylnitrosamineinduced liver fibrosis is manifested by an increase in collagen deposition and severe defenestration of sinusoidal endothelial cells. The HSC-targeted transgene, administered via retrograde intrabiliary infusion in fibrotic rats, successfully reduced liver fibrosis markers alpha-smooth muscle actin and collagen, accompanied by an increase in the expression of DsRed2-HGF near the fibrotic foci. Thus, targeted delivery of HGF gene to hepatic stellate cells increased the transgene expression at the fibrotic foci and strongly enhanced its antifibrotic effects.

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Effects of a New Bioactive Lipid-Based Drug Carrier on Cultured Hepatic Stellate Cells and Liver Fibrosis in Bile Duct-Ligated Rats

Cited by 43 publications

References 38 publications

Emodin protects rat liver from CCl₄-induced fibrogenesis via inhibition of hepatic stellate cells activation

Emodin protects rat liver from CCl₄-induced fibrogenesis via inhibition of hepatic stellate cells activation

Cyclic Arg-Gly-Asp Peptide-Labeled Liposomes for Targeting Drug Therapy of Hepatic Fibrosis in Rats

Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis

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Effects of a New Bioactive Lipid-Based Drug Carrier on Cultured Hepatic Stellate Cells and Liver Fibrosis in Bile Duct-Ligated Rats

Cited by 43 publications

References 38 publications

Emodin protects rat liver from CCl4-induced fibrogenesis via inhibition of hepatic stellate cells activation

Emodin protects rat liver from CCl4-induced fibrogenesis via inhibition of hepatic stellate cells activation

Cyclic Arg-Gly-Asp Peptide-Labeled Liposomes for Targeting Drug Therapy of Hepatic Fibrosis in Rats

Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis

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Emodin protects rat liver from CCl₄-induced fibrogenesis via inhibition of hepatic stellate cells activation

Emodin protects rat liver from CCl₄-induced fibrogenesis via inhibition of hepatic stellate cells activation