Liver fibrosis: mechanisms of immune-mediated liver injury

Xu, Ruonan; Zhang, Zheng; Wang, Fusheng

doi:10.1038/cmi.2011.53

Cited by 142 publications

(116 citation statements)

References 62 publications

(52 reference statements)

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“…4C, 4D). These results indicate that the decrease of total (26,27). In injured liver by CCl 4 , BM-originated T cells (CD3e + ) and dendritic cells (CD11c + ) also increased.…”

Section: Cb1 Mediates the Infiltration Of Bmm In Vivomentioning

confidence: 56%

Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow–Derived Monocytes/Macrophages in a CB1-Dependent Manner

Mai

Yang

Tian

et al. 2015

The Journal of Immunology

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Hepatic injury undergoes significant increases in endocannabinoidsand infiltrations of macrophages, yet the concrete mechanisms of changes in endocannabinoids and the functions of macrophage-expressed cannabinoid receptors (CBs) are unclear. Biosynthetic and degradative enzymes of endocannabinoids revealed a significant change in human fibrotic liver. Meanwhile, we showed dynamic changes of these enzymes and CBs (CB1 and CB2) from 1 to 56 d in carbon tetrachloride–induced murine liver injury. Biosynthetic enzymes (N-acylphosphatidyl-ethanolamine selective phospholipase D and diacylglycerol lipase-α) and CBs were markedly increased, whereas degradative enzymes (fatty acid amidohydrolase and monoacylglycerol lipase) were downregulated. Moreover, these enzymes intimately correlated with the fibrosis parameter [procollagen α1(III)]. Bone marrow–derived monocytes/macrophages (BMM) expressed CBs. Interestingly, CB1 but not CB2 mediated BMM migration through a Boyden chambers assay, and the effect depended on the G(α)i/o/RhoA/ROCK signaling pathway. ICR mice were lethally irradiated and received BM transplants from enhanced GFP transgenic mice. Four weeks later, mice of BM reconstruction were subjected to carbon tetrachloride–induced liver injury. In the chimeric murine model, we found that blockade of CB1 by administration of a CB1 antagonist inhibited the recruitment of BMM into injured liver using immunofluorescence staining and FACS, but it did not have effects on migration of T cells and dendritic cells without CB1 expression. Furthermore, activation of CB1 enhanced cytokine expression of BMM. In vivo, inhibition of CB1 attenuated the inflammatory cytokine level through real-time RT-PCR and cytometric bead array, ameliorating hepatic inflammation and fibrosis. In this study, we identify inactivation of BMM-expressed CB1 as a therapeutic strategy for reducing hepatic inflammation and fibrosis.

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“…4C, 4D). These results indicate that the decrease of total (26,27). In injured liver by CCl 4 , BM-originated T cells (CD3e + ) and dendritic cells (CD11c + ) also increased.…”

Section: Cb1 Mediates the Infiltration Of Bmm In Vivomentioning

confidence: 56%

Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow–Derived Monocytes/Macrophages in a CB1-Dependent Manner

Mai

Yang

Tian

et al. 2015

The Journal of Immunology

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“…Hepatic fibrosis, a pathological outcome of the wound-healing response of the liver to repeated injury, and its end stage, cirrhosis, which is associated with an increased risk of liver failure, portal hypertension and liver cancer [1] , are of great concern worldwide because of the associated high morbidity and mortality [2][3][4] . Hepatic fibrosis results from an imbalance between extracellular matrix (ECM) synthesis and degradation which causes accumulation of ECM deposition.…”

Section: Introductionmentioning

confidence: 99%

Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis

Gao

Chu

et al. 2014

Acta Pharmacol Sin

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Aim: To investigate the anti-fibrosis effects of ginsenoside Rg1 on alcohol-and CCl 4 -induced hepatic fibrosis in rats and to explore the mechanisms of the effects. Methods: Rats were given 6% alcohol in water and injected with CCl 4 (2 mL/kg, sc) twice a week for 8 weeks. Rg1 (10, 20 and 40 mg/kg per day, po) was administered in the last 2 weeks. Hepatic fibrosis was determined by measuring serum biochemical parameters, HE staining, Masson's trichromic staining, and hydroxyproline and α-SMA immunohistochemical staining of liver tissues. The activities of antioxidant enzymes, lipid peroxidation, and Nrf2 signaling pathway-related proteins (Nrf2, Ho-1 and Nqo1) in liver tissues were analyzed. Cultured hepatic stellate cells (HSCs) of rats were prepared for in vitro studies. Results: In the alcohol-and CCl 4 -treated rats, Rg1 administration dose-dependently suppressed the marked increases of serum ALT, AST, LDH and ALP levels, inhibited liver inflammation and HSC activation and reduced liver fibrosis scores. Rg1 significantly increased the activities of antioxidant enzymes (SOD, GSH-Px and CAT) and reduced MDA levels in liver tissues. Furthermore, Rg1 significantly increased the expression and nuclear translocation of Nrf2 that regulated the expression of many antioxidant enzymes. Treatment of the cultured HSCs with Rg1 (1 μmol/L) induced Nrf2 translocation, and suppressed CCl 4 -induced cell proliferation, reversed CCl 4-induced changes in MDA, GPX, PCIII and HA contents in the supernatant fluid and α-SMA expression in the cells. Knockdown of Nrf2 gene diminished these actions of Rg1 in CCl 4 -treated HSCs in vitro. Conclusion: Rg1 exerts protective effects in a rat model of alcohol-and CCl 4 -induced hepatic fibrosis via promoting the nuclear translocation of Nrf2 and expression of antioxidant enzymes.

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“…Fibrosis and cirrhosis of the liver are major causes of morbidity and mortality worldwide and are associated with increasing economic and social impact [9]. Chronic infection with HCV is a leading cause of liver related morbidity and mortality worldwide and predisposes to liver fibrosis and end-stage liver complications [10] (Tables 1-4 and Figures 1-4).…”

Section: Resultsmentioning

confidence: 99%