The Antiproliferative Drug Doxorubicin Inhibits Liver Fibrosis in Bile Duct-Ligated Rats and Can Be Selectively Delivered to Hepatic Stellate Cells in Vivo

Greupink, Rick; Bakker, Hester I.; Bouma, Wilma; Reker‐Smit, Catharina; Meijer, Dirk K. F.; Beljaars, Leonie; Poelstra, Klaas

doi:10.1124/jpet.105.099499

Cited by 53 publications

(30 citation statements)

References 34 publications

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“…HepG2 HCC cells activated HSCs through HBs in our study, in accordance with the above-mentioned findings. The inhibition of HSCs proliferation is considered to be the most important strategy for anti-fibrotic therapy (28). Our results indicated that inhibiting the HBs receptor expression may be a target for the treatment of the liver fibrosis.…”

Section: Discussionmentioning

confidence: 82%

The S protein of hepatitis B virus promotes collagen type I expression in hepatic stellate cells by virtue of hepatocytes

Li¹,

Tu²,

Deng³

et al. 2013

Biomedical Reports

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Abstract. This study was conducted in order to investigate whether hepatitis B surface S protein (HBs) was able to directly or indirectly promote the proliferation and expression of collagen type I (Col I) and α-smooth muscle actin (α-SMA) in hepatic stellate cells (HSCs). The LX-2 human cell line and the HepG2 human hepatocellular carcinoma cell line were employed as HSCs and as hepatocytes, respectively. Recombinant HBs was added to the LX-2 cells for 48 h and the cell proliferation was assessed by the MTT assay. Col I and α-SMA were measured in the supernatant by ELISA, following treatment of the LX-2 and̸or HepG2 cells with recombinant HBs. Transforming growth factor-β1 (TGF-β1) was also determined by ELISA in the HepG2 cell supernatants. The data demonstrated that high concentrations of recombinant HBs (10-50 ng/ml) inhibited the proliferation of LX-2 cells, whereas low concentrations (0.5-5 ng/ml) did not affect LX-2 cell proliferation. After treating LX-2 cells alone with recombinant HBs for 48 h, there was no significant increase in the Col I and α-SMA levels. However, Col I was increased ~1.7-fold in co-cultured (LX-2 and HepG2) cell supernatants following treatment with HBs for 24 h (HBs vs. control group: 48.51±3.51 vs. 28.23±2.55 ng̸ml, respectively). Furthermore, TGF-β1 was significantly increased in the HepG2 cell supernatants following treatment with recombinant HBs. Therefore, we concluded that HBs directly affected the proliferation of HSCs, but promoted the Col I expression in HSCs possibly by virtue of hepatocytes secreting TGF-β1. This may provide a novel explanation of the fibrogenetic mechanism induced by hepatitis B virus-related proteins. IntroductionThe infection with hepatitis B virus (HBV) is a major health concern worldwide. It is estimated that ~350 million individuals are carriers of the hepatitis B surface S protein (HBs) and over one million patients eventually succumb to HBV-related chronic liver diseases annually (1-2). Persistent HBV infection confers a high risk of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC) (3). Three forms of viral particles may be detected in the serum of HBV-infected patients: 42-nm diameter mature virion particles, 22-nm diameter spherical particles and 22-nm diameter filamentous particles (4-5). Subviral particles (22 nm), composed of HBs, are unique in that do not contain viral DNA and usually exceed the numbers of virions by ≥1,000-fold in the patient serum (5). A number of individuals reportedly reached a state of non-replicative infection following persistent anti-virus therapy; however, numerous HBs particles were still detected in their serum and the prolonged immunological response to infection may result in the development of fibrosis in the majority of the patients and eventually lead to the development of cirrhosis, liver failure, or HCC in ~40% of the patients (6). During this process, HBs may play an important role. However, the mechanism underlying the hepatic fibrogenesis induced by HBs has not yet been fully eluci...

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Section: Discussionmentioning

confidence: 82%

The S protein of hepatitis B virus promotes collagen type I expression in hepatic stellate cells by virtue of hepatocytes

Li¹,

Tu²,

Deng³

et al. 2013

Biomedical Reports

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“…The concentration of Dox was measured directly because it naturally fluoresces at 515 nm after excitation with 480 nm light48. Medium containing 10 μM Dox was delivered to the device at 3 μL/min for 32 hours at 25°C.…”

Section: Methodsmentioning

confidence: 99%

A multipurpose microfluidic device designed to mimic microenvironment gradients and develop targeted cancer therapeutics

et al. 2009

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The heterogeneity of cellular microenvironments in tumors severely limits the efficacy of most cancer therapies. We have designed a microfluidic device that mimics the microenvironment gradients present in tumors that will enable the development of more effective cancer therapies. Tumor cell masses were formed within micron-scale chambers exposed to medium perfusion on one side to create linear nutrient gradients. The optical accessibility of the PDMS and glass device enables quantitative transmitted and fluorescence microscopy of all regions of the cell masses. Time-lapse microscopy was used to measure the growth rate and show that the device can be used for long-term efficacy studies. Fluorescence microscopy was used to demonstrate that the cell mass contained viable, apoptotic, and acidic regions similar to in vivo tumors. The diffusion coefficient of doxorubicin was accurately measured, and the accumulation of therapeutic bacteria was quantified. The device is simple to construct, and it can easily be reproduced to create an array of in vitro tumors. Because microenvironment gradients and penetration play critical roles controlling drug efficacy, we believe that this microfluidic device will be vital for understanding the behavior of common cancer drugs in solid tumors and designing novel intratumorally targeted therapeutics.

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“…Furthermore HCS activation is associated with stellate cell proliferation, increased contractility and enhanced extracellular matrix production [11,22,23]. Therefore, HSCs play a crucial role in cellular and molecular events that lead to hepatic fibrosis [6,22,23].…”

Section: Discussionmentioning

confidence: 99%

Microsurgical Extrahepatic Cholestasis in the Rat: A Histopathological Liver Study

Aller

Ortega²,

Sánchez-Patán³

et al. 2008

TOPATJ

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Fibrosis, bile duct proliferation and mast cell hyperplasia characterize extrahepatic cholestasis. We studied these liver alterations in a new microsurgical model of extrahepatic cholestasis in the rat. Male Wistar rats: Sham-operated (n=9) and Microsurgical Cholestasis (n=10). After 4 weeks, a liver morphometric study was carried out using an image analysis system to assess bile proliferation and the fibrosis. The liver expression of alpha-smooth muscle actin was assayed by an immunohistochemical technique and mast cells were also counted. Cholestatic-rats presented portal hypertension, portosystemic circulation, and increased (p=0.0001) plasma bilirubin, alkaline phosphatase, Aspartateaminotransferase, Alanine-aminotransferase, and Lactate-dehydrogenase. Plasma levels of Albumin decreased (p=0.001). Cholestatic-rats showed intense biliary duct proliferation (p=0.0001) and fibrosis (p=0.0001). Mast cells accumulate (p=0.0001) around proliferating bile ducts and fibrous septa. The microsurgical cholestasis in the rat induces fibrosis and hyperplasia of bile ducts and mast cells. Mast cell liver infiltration could be an etiopathogenic remodeling factor in experimental cholestasis.

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The Antiproliferative Drug Doxorubicin Inhibits Liver Fibrosis in Bile Duct-Ligated Rats and Can Be Selectively Delivered to Hepatic Stellate Cells in Vivo

Cited by 53 publications

References 34 publications

The S protein of hepatitis B virus promotes collagen type I expression in hepatic stellate cells by virtue of hepatocytes

The S protein of hepatitis B virus promotes collagen type I expression in hepatic stellate cells by virtue of hepatocytes

A multipurpose microfluidic device designed to mimic microenvironment gradients and develop targeted cancer therapeutics

Microsurgical Extrahepatic Cholestasis in the Rat: A Histopathological Liver Study

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