A novel model of CCl4-induced cirrhosis with ascites in the mouse

Domenicali, Marco; Caraceni, Paolo; Giannone, Ferdinando; Baldassarre, Maurizio; Lucchetti, Giovanna; Quarta, Carmelo; Patti, Corrado; Catani, Lucia; Nanni, Cristina; Lemoli, Roberto M.; Bernardi, Mauro

doi:10.1016/j.jhep.2009.09.008

Cited by 105 publications

(90 citation statements)

References 23 publications

(33 reference statements)

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“…The administration of CCl 4 has been shown to induce advanced stages of liver cirrhosis, although this is not accompanied by the development of HCC. 157 Therefore, CCl 4 treatment of genetically modified mice may lead to the development of models that more closely represent the human condition where HCC develops in cirrhotic livers. Future studies will be needed to investigate these possibilities.…”

Section: Discussionmentioning

confidence: 99%

“…156 Other models of chemically induced liver disease involve the administration of CCl 4 in drinking water, by inhalation, or by subcutaneous or intraperitoneal injections. 151,157 CCl 4 treatment has been shown to induce an advanced stage of liver cirrhosis and related complications, such as ascites decompensation, in both rats and mice. 157,158 However, development of HCC has not been reported.…”

Section: Animal Models Of Liver Cancermentioning

confidence: 99%

“…151,157 CCl 4 treatment has been shown to induce an advanced stage of liver cirrhosis and related complications, such as ascites decompensation, in both rats and mice. 157,158 However, development of HCC has not been reported. In a two-stage chemical model of HCC, CCl 4 administration is accompanied by alcohol supplementation in drinking water.…”

Section: Animal Models Of Liver Cancermentioning

confidence: 99%

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MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches

et al. 2014

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MicroRNAs (miRNAs) constitute a large class of short RNAs (e.g., 20-24 nucleotides in length), whose main function is to posttranscriptionally regulate the expression of protein-coding genes. Their importance in tumorigenesis has been demonstrated over the past decade, and correspondingly, they have emerged as potential therapeutic molecules and targets. Liver cancer is one of the most common neoplastic diseases worldwide, and it currently has a poor prognosis owing to largely ineffective therapeutic options. Liver cancer is also an excellent model for testing miRNA-based therapy approaches as it can be easily targeted with the systemic delivery of oligonucleotides. In recent years, the role of miRNAs in hepatocellular carcinoma (HCC) has been established with molecular studies and the development of animal models. These studies have also provided the basis for evaluating the therapeutic potential of miRNAs, or anti-miRNAs. In general, the safety of miRNAs has been proven and antitumor activity has been observed. Moreover, because of the absence or presence of mild side effects, the prophylactic use of miRNA-based approaches may be foreseen.

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Section: Discussionmentioning

confidence: 99%

Section: Animal Models Of Liver Cancermentioning

confidence: 99%

Section: Animal Models Of Liver Cancermentioning

confidence: 99%

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MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches

et al. 2014

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“…administration of CCl 4 plus phenobarbital in drinking water also induced ascites but to a lesser extent. 26 No obvious ascites were observed in the mice treated with i.p. injection of CCl 4 alone in the present protocol.…”

Section: -Induced Chronic Liver Injury Inflammation Fibrosismentioning

confidence: 96%

“…Ascites were reported in the mice after chronic CCl 4 treatment plus phenobarbital in drinking water, especially after the inhalation protocol. 26 Chronic i.p. administration of CCl 4 plus phenobarbital in drinking water also induced ascites but to a lesser extent.…”

Section: -Induced Chronic Liver Injury Inflammation Fibrosismentioning

confidence: 99%

Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis

Wang

Lafdil

Wang

et al. 2011

The American Journal of Pathology

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Aberrantly hyperactivated STAT3 has been found in human liver cancers as an oncogene; however, STAT3 has also been shown to exert hepatoprotective effects during liver injury. The balancing act that STAT3 plays between hepatoprotection and liver tumorigenesis remains poorly defined. In this study, the diethylnitrosamine (DEN)-induced liver tumor model and the chronic carbon tetrachloride (CCl 4 )-induced liver fibrosis model were both used to investigate the role of STAT3 in liver tumorigenesis. Hepatocyte-specific STAT3 knockout mice were resistant to liver tumorigenesis induced by a single DEN injection, whose tumorigenesis was associated with minimal chronic liver inflammation, injury, and fibrosis. In contrast, long-term CCl 4 treatment resulted in severe hepatic oxidative damage, inflammation, and fibrosis but rarely induced liver tumor formation in wild-type mice. Despite the oncogenic function of STAT3 in DEN-induced liver tumor, hepatocyte-specific STAT3 knockout mice were more susceptible to liver tumorigenesis after 16 weeks of CCl 4 injection, which was associated with higher levels of liver injury, inflammation, fibrosis, and oxidative DNA damage compared with wild-type mice. These findings suggest that the hepatoprotective feature of STAT3 prevents hepatic damage and fibrosis under the condition of persistent inflammatory stress, consequently suppressing injurydriven liver tumor initiation. Once liver tumor cells have developed, STAT3 likely acts as an oncogenic factor to promote tumor growth.

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Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis

et al. 2014

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Activation of the renin angiotensin system resulting in stimulation of angiotensin-II (AngII) type I receptor (AT1R) is an important factor in the development of liver fibrosis. Here, we investigated the role of Janus kinase 2 (JAK2) as a newly described intra-cellular effector of AT1R in mediating liver fibrosis. Fibrotic liver samples from rodents and humans were compared to respective controls. Transcription, protein expression, activation, and localization of JAK2 and downstream effectors were analyzed by realtime polymerase chain reaction, western blotting, immunohistochemistry, and confocal microscopy. Experimental fibrosis was induced by bile duct ligation (BDL), CCl4 intoxication, thioacetamide intoxication or continuous AngII infusion. JAK2 was inhibited by AG490. In vitro experiments were performed with primary rodent hepatic stellate cells (HSCs), Kupffer cells (KCs), and hepatocytes as well as primary human and human-derived LX2 cells. JAK2 expression and activity were increased in experimental rodent and human liver fibrosis, specifically in myofibroblastic HSCs. AT1R stimulation in wild-type animals led to activation of HSCs and fibrosis in vivo through phosphorylation of JAK2 and subsequent RhoA/Rho-kinase activation. These effects were prevented in AT1R–/– mice. Pharmacological inhibition of JAK2 attenuated liver fibrosis in rodent fibrosis models. In vitro, JAK2 and downstream effectors showed increased expression and activation in activated HSCs, when compared to quiescent HSCs, KCs, and hepatocytes isolated from rodents. In primary human and LX2 cells, AG490 blocked AngII-induced profibrotic gene expression. Overexpression of JAK2 led to increased profibrotic gene expression in LX2 cells, which was blocked by AG490. Conclusion Our study substantiates the important cell-intrinsic role of JAK2 in HSCs for development of liver fibrosis. Inhibition of JAK2 might therefore offer a promising therapy for liver fibrosis.

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A novel model of CCl4-induced cirrhosis with ascites in the mouse

Cited by 105 publications

References 23 publications

MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches

MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches

Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis

Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis

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