The relationship between endotoxemia and hepatic endocannabinoids in cirrhotic rats with portal hypertension

Lin, Han Chieh; Yang, Ying‐Ying; Tsai, Tung Hu; Huang, Chih Ming; Huang, Yi Tsau; Lee, Fa Yauh; Liu, Tze Tze; Lee, Shou Dong

doi:10.1016/j.jhep.2010.09.026

Cited by 31 publications

(34 citation statements)

References 25 publications

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“…Furthermore, the finding of low MMPs levels after fibrosis regression has been previously reported by other investigators. [37][38][39][40] As in our study, low MMPs expression was associated with loss of activated HSCs and reduced TGF-b. 37,38,[41][42][43] Finally, as during fibrogenesis, it can be anticipated that the leading role to fibrosis reabsorption would be performed by TIMP-1 expression, the fall of which would unmasks the MMP activity.…”

Section: Endocannabinoids and Liver Cirrhosissupporting

confidence: 73%

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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Section: Endocannabinoids and Liver Cirrhosissupporting

confidence: 73%

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 Molecules: Abnormal Vasculatures in the Splanchnic and Systemic Circulation in Portal Hypertension 7 endotoxemia decreased hepatic endocannabinoid levels and ameliorated the hyperdynamic circulatory syndrome in those rats (Lin, et al 2011). Fig.…”

Section: Endocannabinoidsmentioning

confidence: 97%

The Molecules: Abnormal Vasculatures in the Splanchnic and Systemic Circulation in Portal Hypertension"

Iwakiri¹

2012

Portal Hypertension - Causes and Complications

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“…59,68e70 Further studies have shown that endotoxin-induced TNFa production is the key factor to induce liver injury and promote hepatic fibrogenesis. 68,70 Additionally, thromboxane A 2 has already proved to be a potent vasoconstrictor that is involved in the mechanism of increased IHR in cirrhosis. 6,54 Anandamide is an endocannabinoid that demonstrates increasing IHR through the release of thromboxanes A 2 in cirrhotic livers.…”

Section: (4) Endocannabinoidsmentioning

confidence: 99%

Alteration of intrahepatic microcirculation in cirrhotic livers

Yang

Lin

2015

Journal of the Chinese Medical Association

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From a hemodynamic point of view, hepatic vascular resistance and portal inflow determine the level of portal pressure. Factors that determine hepatic vascular resistance include both structural and dynamic components. Among the structural components are histological characteristics such as steatosis, fibrosis, regeneration nodules, and neo-angiogenesis. Dynamic structures include cells with contractile properties such as hepatocytes, hepatic stellate cells, sinusoidal endothelial cells, and Kupffer cells. The contributions of the interactions between four cells in cirrhotic livers resulted in hepatic endothelial dysfunction, hepatic microcirculatory dysfunction, hepatic venous dysregulation, hepatic fibrogenesis, and subsequently increased intrahepatic resistance and portal hypertension in cirrhosis. The pathogenic mechanisms that trigger the associated abnormalities in hepatic microcirculations include persistent endotoxemia, increased hepatic oxidative stress, activated endocannabinoids substances, pathogenic sinusoidal remodeling, and hypoperfusion in cirrhotic livers. Cumulative data suggested that various therapeutic strategies targeting hepatic microcirculation provided effective improvement of the systemic abnormalities of cirrhosis. Accordingly, the mechanistic and therapeutic approaches focusing on the disarrangement of hepatic microcirculation will be introduced in this article.

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The relationship between endotoxemia and hepatic endocannabinoids in cirrhotic rats with portal hypertension

Cited by 31 publications

References 25 publications

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

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

The Molecules: Abnormal Vasculatures in the Splanchnic and Systemic Circulation in Portal Hypertension"

Alteration of intrahepatic microcirculation in cirrhotic livers

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