Inhibition of hepatic tumour necrosis factor‐α attenuates the anandamide‐induced vasoconstrictive response in cirrhotic rat livers

Yang, Ying‐Ying; Lee, Kuei–Chuan; Huang, Yo-Ping; Lee, Fa-Yauh; Chau, Ga-Yang; Loong, Che‐Chuan; Lin, Han‐Chieh; Lee, Shou‐Dong

doi:10.1111/j.1478-3231.2009.01983.x

Cited by 14 publications

(10 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…What are the possible mechanisms for TNFα to release endocannabinoids in the cirrhotic heart? Previous studies found that macrophages, in response to endotoxin, secrete TNFα which further increases oxidative stress and activates the endocannabinoid system [2,3,31,32]. Our results, combined with previous studies, imply that neutralizing TNFα relieves cardiac oxidative stress and subsequently suppresses the local release of endocannabinoids in fibro-cholestatic hearts (Fig.…”

Section: Discussionsupporting

confidence: 81%

Mechanisms of TNFα-induced cardiac dysfunction in cholestatic bile duct-ligated mice: Interaction between TNFα and endocannabinoids

Yang

Liu

Nam

et al. 2010

Journal of Hepatology

Self Cite

View full text Add to dashboard Cite

Background & Aims Chronic liver disease is associated with endotoxemia, oxidative stress, increased endocannabinoids and decreased cardiac responsiveness. Endocannabinoids activate the tumor necrosis factor-alpha (TNFα)–nuclear factor κB (NFκB) pathway. However, how they interact with each other remains obscure. We therefore aimed to clarify the relationship between the TNFα–NFκB pathway and endocannabinoids in the pathogenesis of cardiodepression of cholestatic bile duct ligated (BDL) mice. Methods BDL mice with TNFα knockout (TNFα−/−) and infusion of anti-TNFα antibody were used. Cardiac mRNA and protein expression of NFκBp65, c-Jun-N-terminal kinases (JNK), p38 mitogen-activated protein kinase (p38MAPK), extracelullar-signal-regulated kinase (ERK), inducible nitric oxide synthase (iNOS), Copper/Zinc and Magnesium-superoxide dismutase (Cu/Zn- and Mn-SOD), cardiac anandamide, 2-arachidonoylglycerol (2-AG), nitric oxide (NOx) and glutathione, and plasma TNFα were measured. The effects of TNFα, cannabinoid receptor (CB1) antagonist AM251 and the endocannabinoid reuptake inhibitor UCM707, on the contractility of isolated cardiomyocytes, were assessed. Results In BDL mice, cardiac mRNA and protein expression of NFκBp65, p38MAPK, iNOS, NOx, anandamide, and plasma TNFα were increased, whereas glutathione, Cu/Zn-SOD, and Mn-SOD were decreased. Cardiac contractility was blunted in BDL mice. Anti-TNFα treatment in BDL mice decreased cardiac anandamide and NOx, reduced expression of NFκBp65, p38MAPK, and iNOS, enhanced expression of Cu/Zn-SOD and Mn-SOD, increased reductive glutathione and restored cardiomyocyte contractility. TNFα-depressed contractility was worsened by UCM707, whereas AM251 improved contractility. Conclusions Increased TNFα, acting via NFκB–iNOS and p38MAPK signaling pathways, plays an important role in the pathogenesis of cardiodepression in BDL mice. TNFα also suppressed contractility by increasing oxidative stress and endocannabinoid activity.

show abstract

Section: Discussionsupporting

confidence: 81%

Mechanisms of TNFα-induced cardiac dysfunction in cholestatic bile duct-ligated mice: Interaction between TNFα and endocannabinoids

Yang

Liu

Nam

et al. 2010

Journal of Hepatology

Self Cite

View full text Add to dashboard Cite

show abstract

“…6 Our study also revealed that chronic inhibition of endogenous TNFa by thalidomide will attenuate the anandamide-mediated vasoconstriction in cirrhotic livers. 68,69 7. Interaction between endotoxemia and endocannabinoids in cirrhosis-HED Endotoxemia-related activated endocannabinoid systems induce HED and subsequently increases IHR in Figure 2.…”

Section: (4) Endocannabinoidsmentioning

confidence: 99%

Alteration of intrahepatic microcirculation in cirrhotic livers

Yang

Lin

2015

Journal of the Chinese Medical Association

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…TNFα increases the intrahepatic resistance due to activation of macrophages and hepatic stellate cells, whereas it leads to extra-hepatic vasodilation and increased portal-venous inflow through induction of nitric oxide. Taken together, both processes aggravate portal hypertension [5]–[10].…”

Section: Introductionmentioning

confidence: 97%

Soluble TNF-Alpha-Receptors I Are Prognostic Markers in TIPS-Treated Patients with Cirrhosis and Portal Hypertension

et al. 2013

View full text Add to dashboard Cite

BackgroundTNFα levels are increased in liver cirrhosis even in the absence of infection, most likely owing to a continuous endotoxin influx into the portal blood. Soluble TNFα receptors (sTNFR type I and II) reflect release of the short-lived TNFα, because they are cleaved from the cells after binding of TNFα. The aims were to investigate the circulating levels of soluble TNFR-I and -II in cirrhotic patients receiving TIPS.MethodsForty-nine patients with liver cirrhosis and portal hypertension (12 viral, 37 alcoholic) received TIPS for prevention of re-bleeding (n = 14), therapy-refractory ascites (n = 20), or both (n = 15). Portal and hepatic venous blood was drawn in these patients during the TIPS procedure and during the control catheterization two weeks later. sTNFR-I and sTNFR-II were measured by ELISA, correlated to clinical and biochemical characteristics.ResultsBefore TIPS insertion, sTNFR-II levels were lower in portal venous blood than in the hepatic venous blood, as well as in portal venous blood after TIPS insertion. No significant differences were measured in sTNFR-I levels. Hepatic venous levels of sTNFR-I above 4.5 ng/mL (p = 0.036) and sTNFR-II above 7 ng/mL (p = 0.05) after TIPS insertion were associated with decreased survival. A multivariate Cox-regression survival analysis identified the hepatic venous levels of sTNFR-I (p = 0.004) two weeks after TIPS, and Child score (p = 0.002) as independent predictors of mortality, while MELD-score was not.ConclusionHepatic venous levels of sTNFR-I after TIPS insertion may predict mortality in patients with severe portal hypertension.

show abstract

Inhibition of hepatic tumour necrosis factor‐α attenuates the anandamide‐induced vasoconstrictive response in cirrhotic rat livers

Abstract: Thalidomide decreased the PVP and IHR through the attenuation of anandamide-induced constrictive response, decreasing the production of TNF-alpha, IL-6 and TXA(2) in the liver and the suppression of hepatic fibrogenesis of rats with biliary cirrhosis of this study.

Cited by 14 publications

References 47 publications

Mechanisms of TNFα-induced cardiac dysfunction in cholestatic bile duct-ligated mice: Interaction between TNFα and endocannabinoids

Mechanisms of TNFα-induced cardiac dysfunction in cholestatic bile duct-ligated mice: Interaction between TNFα and endocannabinoids

Alteration of intrahepatic microcirculation in cirrhotic livers

Soluble TNF-Alpha-Receptors I Are Prognostic Markers in TIPS-Treated Patients with Cirrhosis and Portal Hypertension

Contact Info

Product

Resources

About