Antagonism of the cannabinoid CB-1 receptor protects rat liver against ischaemia-reperfusion injury complicated by endotoxaemia

Caraceni, Paolo; Pertosa, Anna Maria; Giannone, Ferdinando; Domenicali, Marco; Grattagliano, Ignazio; Príncipe, Alessandro; Mastroleo, C; Perrelli, Maria Giulia; Cutrìn, Juan Carlos; Trevisani, Franco; Croci, Tiziano; Bernardi, Mauro

doi:10.1136/gut.2007.147652

Cited by 49 publications

(40 citation statements)

References 40 publications

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“…An increase in de novo hepatic lipogenesis and a decrease of total energy expenditure by CB1 agonists were absent in both CB1 Blockade of CB1 improved hemodynamic abnormalities and prevented progression of ascites (30). Liver regeneration and I/R injury were associated with a marked increase of CB1 expression in hepatocytes (23,31). Blockade or ablation of CB1 showed a protective role in I/R injury and delayed liver regeneration.…”

Section: Discussionmentioning

confidence: 92%

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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Section: Discussionmentioning

confidence: 92%

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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“…24 TNF-a and MCP-1 have an important role in the development of fibrosis as pro-inflammatory molecules contributing to the activation of HSC and to the recruitment of myofibroblasts, macrophages and other effector cells to sites of tissue injury. 16,17 As we have recently showed in a model of acute liver injury produced by ischemia-reperfusion complicated by endotoxemia, 13 Rimonabant appears to exert its protective activity also by promoting the synthesis of IL-10 and SOCS-3. IL-10 is a major anti-inflammatory cytokines, which restrains the immune response under various stimuli 25,26 and may reduce fibrogenesis by downregulating pro-fibrogenic cytokines, including TGF-b and TNF-a 27 and fibrogenetic mediators, such as TIMP-1.…”

Section: Endocannabinoids and Liver Cirrhosismentioning

confidence: 99%

“…The liver tissue was homogenized in 1% Triton X-100 lysis buffer supplemented with a cocktail of protease and phosphatase inhibitors. 13 The total protein samples (40 mg) were subjected to SDS-PAGE electrophoresis, transferred to PVDF membranes (Millipore Corporation, Billerica, MA, USA) and incubated overnight with mouse anti-a-SMA antibody (1:500; Dako Cytomation). After incubation with horseradish peroxidase-conjugated antimouse antibody, the signals were detected by enhanced chemiluminescence with an ECL kit (Amersham Biosciences, Freiburg, Germany).…”

Section: Assessment Of Activated Hepatic Stellate Cells (Hscs) Bymentioning

confidence: 99%

Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl4-induced advanced cirrhosis

Giannone

Baldassarre

Domenicali

et al. 2012

Laboratory Investigation

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The endocannabinoid system is involved in the pathogenesis of liver fibrosis. Although many substances have been proved to reduce fibrosis in experimental models of chronic liver injury, most of them appear to be effective only if given as a prophylactic or early treatment. This study aimed to explore the effect of pharmacological antagonism of the endocannabinoid cannabinoid type 1 (CB1) receptor started after the stage of full-blown cirrhosis had been reached. Wistar-Han rats with carbon tetrachloride (CCl 4 )-induced cirrhosis were randomized to receive the CB1 receptor antagonist Rimonabant (10 mg/kg/day) or the vehicle for 2 weeks. Age-matched healthy rats served as controls. Liver fibrosis was assessed using Sirius red staining, hydroxyproline concentration and a-smooth muscle actin expression. Hepatic gene expression of mediators of fibrogenesis and inflammation were evaluated by real-time PCR. We also assessed the hepatic expression of CB1 and CB2 receptors and that of the enzymes implicated in the endocannabinoid metabolism. Fibrosis was significantly reduced in rats treated with Rimonabant compared with rats receiving the vehicle. CB1 receptor antagonism limited the gene upregulation of fibrogenic and inflammatory mediators occurring in untreated cirrhotic rats. CB1 and CB2 receptor expression was increased in cirrhotic animals. Interestingly, pharmacological CB1 receptor antagonism was associated with a further induction of the CB2 receptor expression. Regression of fibrosis can be achieved by pharmacological blockade of the CB1 receptor even when started in an advanced stage of the disease. This effect is associated with the suppression of pro-fibrogenic and inflammatory mediators and may have been indirectly favoured by the induction of CB2 receptor expression.

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“…148 physiological role there. A number of recent studies have demonstrated a protective role for the activation of the CB2 receptor in several pathological conditions of the liver: in liver fibrosis via reduction in the accumulation of fibrogenic cells; in hepatic ischemia/reperfusion injury via attenuation of the inflammatory response; in hepatic encephalopathy via stimulation of brain AMP-activated protein kinase; and in autoimmune hepatitis via upregulation of regulatory T cells and down-regulation of inflammatory cytokines (Julien et al, 2005;Avraham et al, 2006;Bá tkai et al, 2007;Mendez-Sanchez et al, 2007;Hegde et al, 2008;Caraceni et al, 2009b). Most of these studies have been reviewed previously (Caraceni et al, 2009a).…”

Section: Cytochrome P450-mediated Anandamide Oxidation and Liver Pmentioning

confidence: 99%

Oxidation of the Endogenous Cannabinoid Arachidonoyl Ethanolamide by the Cytochrome P450 Monooxygenases: Physiological and Pharmacological Implications

2010

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Antagonism of the cannabinoid CB-1 receptor protects rat liver against ischaemia-reperfusion injury complicated by endotoxaemia

Cited by 49 publications

References 40 publications

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

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

Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl4-induced advanced cirrhosis

Oxidation of the Endogenous Cannabinoid Arachidonoyl Ethanolamide by the Cytochrome P450 Monooxygenases: Physiological and Pharmacological Implications

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