Hepatitis C virus (HCV) protein expression enhances hepatic fibrosis in HCV transgenic mice exposed to a fibrogenic agent.
Chouteau Philippe,Defer Nicole,Florimond Alexandre,Caldéraro Julien,Higgs Martin,Gaudin Aurore,Mérour Emilie,Dhumeaux Daniel,Lerat Hervé,Pawlotsky Jean-Michel
Journal of hepatology
BACKGROUND & AIMS:During chronic HCV infection, activation of fibrogenesis appears to be principally related to local inflammation. However, the direct role of hepatic HCV protein expression in fibrogenesis remains unknown. METHODS:We used transgenic mice expressing the full length HCV open reading frame exposed to a 'second hit' of the fibrogenic agent carbon tetrachloride (CCl(4)). Both acute and chronic liver injuries were induced in these mice by CCl(4) injections. Liver injury, expression of matrix re-modeling genes, reactive oxygen species (ROS), inflammation, hepatocyte proliferation, ductular reaction and hepatic progenitor cells (HPC) expansion were examined. RESULTS:After CCl(4) treatment, HCV transgenic mice exhibited enhanced liver fibrosis, significant changes in matrix re-modeling genes and increased ROS production compared to wild type littermates despite no differences in the degree of local inflammation. This increase was accompanied by a decrease in hepatocyte proliferation, which appeared to be due to delayed hepatocyte entry into the S phase. A prominent ductular reaction and hepatic progenitor cell compartment expansion were observed in transgenic animals. These observations closely mirror those previously made in HCV-infected individuals. CONCLUSIONS:Together, these results demonstrate that expression of the HCV proteins in hepatocytes contributes to the development of hepatic fibrosis in the presence of other fibrogenic agents. In the presence of CCl(4), HCV transgenic mice display an intra-hepatic re-organization of several key cellular actors in the fibrogenic process.
10.1016/j.jhep.2012.04.019
Low-molecular-weight fibroblast growth factor 2 attenuates hepatic fibrosis by epigenetic down-regulation of Delta-like1.
Pan Ruo-Lang,Xiang Li-Xin,Wang Ping,Liu Xiao-Yuan,Nie Li,Huang Wendong,Shao Jian-Zhong
Hepatology (Baltimore, Md.)
UNLABELLED:Liver fibrosis, a major cause of end-stage liver diseases, is closely regulated by multiple growth factors and cytokines. The correlation of fibroblast growth factor 2 (FGF2) with chronic liver injury has been reported, but the exact functions of different FGF2 isoforms in liver fibrogenesis remain unclear. Here, we report on the differential expression patterns and functions of low- and high-molecular-weight FGF2 (namely, FGF2(lmw) and FGF2(hmw) , respectively) in hepatic fibrogenesis using a CCl4 -induced mouse liver fibrosis model. FGF2(hmw) displayed a robust increase in CCl4 -induced hepatic fibrosis and promoted fibrogenesis. In contrast, endogenous FGF2(lmw) exhibited a slight increase in hepatic fibrosis and suppressed this pathological progression. Moreover, exogenous administration of recombinant FGF2(lmw) potently ameliorated CCl4 -induced liver fibrosis. Mechanistically, we showed that FGF2(lmw) treatment attenuated hepatic stellate cell activation and fibrosis by epigenetic down-regulation of Delta-like 1 expression through the p38 mitogen-activated protein kinase pathway. CONCLUSION:FGF2(lmw) and FGF2(hmw) have distinct roles in liver fibrogenesis. These findings demonstrate a potent antifibrotic effect of FGF2(lmw) administration, which may provide a novel approach to treat chronic liver diseases.
10.1002/hep.27649
Gadolinium accumulation and fibrosis in the liver after administration of gadoxetate disodium in a rat model of active hepatic fibrosis.
Hope Thomas A,Doherty Amanda,Fu Yanjun,Aslam Rizwan,Qayyum Aliya,Brasch Robert C
Radiology
PURPOSE:To evaluate the effect of gadoxetate disodium on fibrosis in a rat model of active hepatic fibrosis. MATERIALS AND METHODS:The local committee for animal research approved this study. Hepatic fibrosis was induced during 12 weeks of intraperitoneal injection of carbon tetrachloride (CCl(4)). Gadoxetate disodium was administered at 10 mmol/kg for 5 consecutive days starting after the final dose of CCl(4) (clinical dose of gadoxetate disodium is 0.25 mmol/kg). Three groups of Sprague-Dawley rats were studied. Group 1 consisted of six rats treated only with gadoxetate disodium, group 2 consisted of nine rats treated only with CCl(4), and group 3 consisted of nine rats treated with both gadoxetate disodium and CCl(4). Seven days after the final injection of gadoxetate disodium, the rats were sacrificed, and histologic findings and gadolinium deposition in the liver were examined. Fibrosis stage and gadolinium deposition were compared by using the Mann-Whitney test and Student t test. RESULTS:Fibrosis grading in groups 2 and 3 did not differ significantly (mean Batts-Ludwig fibrosis stage in group 2 was 2.67 and in group 3 was 2.78, P = .70; mean Ishak fibrosis stage in group 2 was 3.89 and in group 3 was 4.11, P = .71). Gadolinium deposition in the liver was slightly increased in group 3 in comparison to group 1 (3.2 ppm versus 4.0 ppm, P = .01), although this reversed when corrected as a percentage of total injected dose (0.022% versus 0.017%, P = .003). CONCLUSION:The high-dose administration of gadoxetate disodium in the setting of active hepatic fibrosis was not associated with increased fibrosis, suggesting that gadoxetate disodium does not incite a nephrogenic systemic fibrosis-like fibrotic change in the setting of active hepatic inflammation.
10.1148/radiol.12112453
3,3'-Diindolylmethane ameliorates experimental hepatic fibrosis via inhibiting miR-21 expression.
Zhang Zhengping,Gao Zhongfei,Hu Wei,Yin Shan,Wang Chunming,Zang Yuhui,Chen Jiangning,Zhang Junfeng,Dong Lei
British journal of pharmacology
BACKGROUND AND PURPOSE:Hepatic fibrosis is a type of liver disease characterized by excessive collagen deposition produced by activated hepatic stellate cells (HSCs), and no appropriate drug treatment is available clinically. The microRNA, miR-21 exhibits an important role in the pathogenesis and progression of hepatic fibrosis. 3,3'-Diindolylmethane (DIM) is a natural autolytic product in plants and can down-regulate miR-21 expression. Here we have assessed the therapeutic effects of DIM against hepatic fibrosis and investigated the underlying mechanisms. EXPERIMENTAL APPROACH:The effects of DIM on HSC activation were measured by analysing the expression of α-smooth muscle actin and collagen I in both HSC-T6 cell line and primary HSCs. Expression of miR-21 was also measured after DIM treatment and the therapeutic effect of DIM was further studied in vivo, using the model of hepatic fibrosis induced by thioacetamide in mice. The antagonist oligonucleotide, antagomir-21, was also used to suppress the effects of miR-21. KEY RESULTS:DIM suppressed the central TGF-β signalling pathway underlying HSC activation by down-regulating the expression of miR-21. The decreased miR-21 expression was achieved by inhibiting the activity of the transcription factor, AP-1. Moreover, DIM blunted the activation phenotype of primary HSCs. Administration of DIM in vivo attenuated liver fibrosis induced by thioacetamide, as assessed by collagen deposition and profiles of profibrogenic markers. CONCLUSIONS AND IMPLICATIONS:DIM shows potential as a therapeutic agent for the treatment of hepatic fibrosis.
10.1111/bph.12323
Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development.
Theranostics
Liver damage and fibrosis are precursors of hepatocellular carcinoma (HCC). In HCC patients, sorafenib-a multikinase inhibitor drug-has been reported to exert anti-fibrotic activity. However, incomplete inhibition of RAF activity by sorafenib may also induce paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in malignant cells. The consequence of this effect in non-malignant disease (hepatic fibrosis) remains unknown. This study aimed to examine the effects of sorafenib on activated hepatic stellate cells (HSCs), and develop effective therapeutic approaches to treat liver fibrosis and prevent cancer development. We first examined the effects of sorafenib in combination with MEK inhibitors on fibrosis pathogenesis and . To improve the bioavailability and absorption by activated HSCs, we developed CXCR4-targeted nanoparticles (NPs) to co-deliver sorafenib and a MEK inhibitor to mice with liver damage. We found that sorafenib induced MAPK activation in HSCs, and promoted their myofibroblast differentiation. Combining sorafenib with a MEK inhibitor suppressed both paradoxical MAPK activation and HSC activation , and alleviated liver fibrosis in a CCl-induced murine model of liver damage. Furthermore, treatment with sorafenib/MEK inhibitor-loaded CXCR4-targeted NPs significantly suppressed hepatic fibrosis progression and further prevented fibrosis-associated HCC development and liver metastasis. Our results show that combined delivery of sorafenib and a MEK inhibitor via CXCR4-targeted NPs can prevent activation of ERK in activated HSCs and has anti-fibrotic effects in the CCl-induced murine model. Targeting HSCs represents a promising strategy to prevent the development and progression of fibrosis-associated HCC.
10.7150/thno.21168
Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells.
Tan Zhongming,Liu Qianghui,Jiang Runqiu,Lv Long,Shoto Siamak S,Maillet Isabelle,Quesniaux Valerie,Tang Junwei,Zhang Wenjie,Sun Beicheng,Ryffel Bernhard
Cellular & molecular immunology
Liver fibrosis is a consequence of chronic liver disease, causing morbidity and mortality. Interleukin-33 (IL-33) is a critical mediator of inflammation, which may be involved in the development of liver fibrosis. Here, we investigated the role of IL-33 in human patients and experimental bile-duct ligation (BDL)-induced fibrosis in mice. We report increased hepatic IL-33 expression in the murine BDL model of fibrosis and in surgical samples obtained from patients with liver fibrosis. Liver injury, inflammatory cell infiltration and fibrosis were reduced in the absence of the IL-33/ST2 receptor, and the activation of hepatic stellate cells (HSCs) was decreased in ST2-deficient mice. Recombinant IL-33 activated HSCs isolated from C57BL/6 mice, leading to the expression of IL-6, TGF-β, α-SMA and collagen, which was abrogated in the absence of ST2 or by pharmacological inhibition of MAPK signaling. Finally, administration of recombinant IL-33 significantly increased hepatic inflammation in sham-operated BL6 mice but did not enhance BDL-induced hepatic inflammation and fibrosis. In conclusion, BDL-induced liver inflammation and fibrosis are dependent on ST2 signaling in HSCs, and therefore, the IL-33/ST2 pathway may be a potential therapeutic target in human patients with chronic hepatitis and liver fibrosis.
10.1038/cmi.2016.63