Abstract:
BACKGROUND & AIMS:Toll-like receptor 4 (TLR4) plays an essential role in mediating organ injury in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Herein, we assess whether inhibiting TLR4 signaling can ameliorate liver failure and serve as a potential treatment. METHODS:Circulating TLR4 ligands and hepatic TLR4 expression were measured in plasma samples and liver biopsies from patients with cirrhosis. TAK-242 (TLR4 inhibitor) was tested in vivo (10 mg/kg intraperitoneally) in rodent models of ACLF (bile duct ligation + lipopolysaccharide [LPS]; carbon tetrachloride + LPS) and ALF (galactosamine + LPS) and in vitro on immortalized human monocytes (THP-1) and hepatocytes (HHL5). The in vivo therapeutic effect was assessed by coma-free survival, organ injury and cytokine release and in vitro by measuring IL-6, IL-1β or cell injury (TUNEL), respectively. RESULTS:In patients with cirrhosis, hepatic TLR4 expression was upregulated and circulating TLR4 ligands were increased (p <0.001). ACLF in rodents was associated with a switch from apoptotic cell death in ALF to non-apoptotic forms of cell death. TAK-242 reduced LPS-induced cytokine secretion and cell death (p = 0.002) in hepatocytes and monocytes in vitro. In rodent models of ACLF, TAK-242 administration improved coma-free survival, reduced the degree of hepatocyte cell death in the liver (p <0.001) and kidneys (p = 0.048) and reduced circulating cytokine levels (IL-1β, p <0.001). In a rodent model of ALF, TAK-242 prevented organ injury (p <0.001) and systemic inflammation (IL-1β, p <0.001). CONCLUSION:This study shows that TLR4 signaling is a key factor in the development of both ACLF and ALF; its inhibition reduces the severity of organ injury and improves outcome. TAK-242 may be of therapeutic relevance in patients with liver failure. LAY SUMMARY:Toll-like receptor 4 (or TLR4) mediates endotoxin-induced tissue injury in liver failure and cirrhosis. This receptor sensitizes cells to endotoxins, which are produced by gram-negative bacteria. Thus, inhibiting TLR4 signaling with an inhibitor (TAK-242) ameliorates organ injury and systemic inflammation in rodent models of acute and acute-on-chronic liver failure.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Engelmann C,Sheikh M,Sharma S,Kondo T,Loeffler-Wirth H,Zheng YB,Novelli S,Hall A,Kerbert AJC,Macnaughtan J,Mookerjee R,Habtesion A,Davies N,Ali T,Gupta S,Andreola F,Jalan Rdoi
10.1016/j.jhep.2020.01.011subject
Has Abstractpub_date
2020-07-01 00:00:00pages
102-112issue
1eissn
0168-8278issn
1600-0641pii
S0168-8278(20)30028-3journal_volume
73pub_type
杂志文章abstract:BACKGROUND & AIMS:Disturbance in lipid metabolism is one of the features of chronic hepatitis C, being a crucial determinant of the progression of liver fibrosis. Experimental studies have revealed that the core protein of hepatitis C virus (HCV) induces steatosis. METHODS:The activities of fatty acid metabolizing enz...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2010.07.039
更新日期:2011-03-01 00:00:00
abstract::To summarize, nowadays it seems clear that in patients with cirrhosis: (a) the pulmonary circulation is usually markedly dilated. (b) This vasodilation is due to a loss of vascular tone and it is characterized by a poor (or even absent) vascular reactivity in front of the hypoxic stimulus. (c) This abnormal behaviour ...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/0168-8278(90)90061-u
更新日期:1990-03-01 00:00:00
abstract:BACKGROUND/AIMS:A 4977-base pair deletion has been detected in the hepatic mitochondrial DNA of alcoholic patients with microvesicular steatosis, a lesion ascribed to impaired mitochondrial beta-oxidation. However, only a single deletion had been looked for in this previous study, and it could not be determined whether...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(97)80286-3
更新日期:1997-07-01 00:00:00
abstract:BACKGROUND/AIMS:Most hepatocellular carcinomas are still discovered at an advanced stage and are left untreated as large hepatocellular carcinomas are contraindications to liver transplantation and percutaneous ethanol injection and are usually considered as poor indications for liver resection. The aim of this study w...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(99)80319-5
更新日期:1999-12-01 00:00:00
abstract::We have studied the roles of immunoprophylaxis, patient selection policy and coexistent hepatitis D virus infection in the outcome of 56 HBsAg-positive elective liver transplant recipients. Twenty-nine unselected patients not treated with immunoprophylaxis formed group 1 and were compared to a recent consecutive serie...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章
doi:10.1016/s0168-8278(05)80396-4
更新日期:1994-08-01 00:00:00
abstract:BACKGROUND & AIMS:We previously showed that Reptin is overexpressed in hepatocellular carcinoma (HCC), and that in vitro depletion of Reptin with siRNAs led to HCC cell growth arrest and apoptosis. Here, we asked whether in vivo targeting of Reptin in established tumours had a therapeutic effect. METHODS:We used lenti...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2009.12.029
更新日期:2010-05-01 00:00:00
abstract:BACKGROUND/AIMS:Except for bleeding complications, other serious adverse reactions of coumarin anticoagulants such as hepatotoxicity or skin necrosis are comparatively rare. Nonetheless, a small number of coumarin-induced (sub-) acute liver failures has been published. METHODS:A retrospective analysis was performed of...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.03.010
更新日期:2004-07-01 00:00:00
abstract::Liver fibrosis is one of the most important factors of disturbed liver function, but could not be measured by simple blood tests until recently. Among several parameters used for this purpose, the aminoterminal procollagen type III peptide (PIIIP) appears to be the most widely accepted. Studies conducted in several cl...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(85)80069-6
更新日期:1985-01-01 00:00:00
abstract:BACKGROUND/AIMS:Hepatic stellate cells (HSCs) are known to play a role in hepatic regeneration. We investigated hepatocyte/HSC interaction and HSC activation at various times after 70% partial hepatectomy (PHx) in the rat. METHODS:The hepatic microcirculation was studied using intravital fluorescence microscopy (IVFM)...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.02.005
更新日期:2004-06-01 00:00:00
abstract:BACKGROUND/AIMS:S-adenosylmethionine (SAM) is a thiol-containing compound with known therapeutic affects on cholestasis and hepatotoxicity. The aim of this study was to investigate the effect of SAM on the prevention of mitochondrial injury induced by hepatic ischemia and reperfusion. METHODS/RESULTS:Rats were subject...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(00)00045-3
更新日期:2001-03-01 00:00:00
abstract:BACKGROUND & AIMS:Visceral adiposity is associated with hepatic steatosis, inflammation, and fibrosis in non-alcoholic fatty liver disease (NAFLD). The visceral adiposity index (VAI), a novel marker of visceral fat distribution and dysfunction, has been correlated with histology in hepatitis C. We assessed the ability ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2012.03.013
更新日期:2012-08-01 00:00:00
abstract:BACKGROUND/AIMS:To evaluate the fluctuating course of serum HBV-DNA levels during the natural history of chronic HBV infection in the general population of North-Eastern Greece, in association with liver disease progression. METHODS:Two hundred and sixty-three adults with chronic HBV, median 34 years of age, were rand...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2008.06.009
更新日期:2008-12-01 00:00:00
abstract:BACKGROUND/AIMS:Hepatitis C virus (HCV) is a major etiologic agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The aim of this study was to elucidate pathological effects of HCV-core protein on liver cells. METHODS:We have generated transgenic mice carrying HCV-core cDNA (Px-core) and pathologically...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(00)80280-9
更新日期:2000-09-01 00:00:00
abstract::Intracellular ion homeostasis in liver cell is accomplished through the concerted action of ion pumps, carriers and channels. Description of these elements includes the Na+/K+-ATPase, Na+/H+- and Cl-/ HCO3(-)-exchange and Na+-HCO-3(-)- and Na(+)-K(+)-2 Cl(-)-cotransport as well as K+-, Cl(-)-, Na+ and nonselective cat...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:
更新日期:1996-01-01 00:00:00
abstract:BACKGROUND & AIMS:The accuracy of creatinine-based estimated GFR (eGFR) in assessing the prevalence of chronic kidney disease (CKD) and associated mortality after liver transplantation (LTx) is unknown. Using measured GFR (mGFR) by iothalamate clearance, we determined the prevalence of the entire spectrum of renal dysf...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2014.03.034
更新日期:2014-08-01 00:00:00
abstract:BACKGROUND & AIMS:Hepatocyte-like cells, differentiated from different stem cell sources, are considered to have a range of possible therapeutic applications, including drug discovery, metabolic disease modelling, and cell transplantation. However, little is known about how stem cells differentiate into mature and func...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2014.07.025
更新日期:2014-12-01 00:00:00
abstract::Chronic liver diseases are a serious health problem worldwide. The current gold standard to assess structural liver damage is through a liver biopsy which has several disadvantages. A non-invasive, simple and non-expensive test to diagnose liver pathology would be highly desirable. Protein glycosylation has drawn the ...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2008.12.010
更新日期:2009-03-01 00:00:00
abstract:BACKGROUND/METHODS:In order to define the clinical significance of borderline levels of IgM anti-HBc in chronic hepatitis B patients, we followed up 89 untreated hepatitis B patients (19 HBeAg pos and 70 anti-HBe pos) for 1 year, with monthly monitoring of IgM anti-HBc using a highly sensitive quantitative microparticl...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(96)80233-9
更新日期:1996-11-01 00:00:00
abstract:BACKGROUND/AIMS:Hepatitis B virus (HBV) infection in extrahepatic tissues is controversial. To clarify whether episomal HBV can infect nonhepatic tissues, we investigated the molecular forms of HBV in the lymphatic cells of inactive HBV carriers who lacked viremia, thus avoiding contamination with HBV genomes originati...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2005.01.016
更新日期:2005-06-01 00:00:00
abstract::The presence of hepatitis B virus DNA (HBV-DNA) in the peripheral blood mononuclear cells (PBMC) of 29 anti-HIV symptomless carriers (eleven HBeAg positive, eleven anti-HBe positive and seven HBsAg negative) and of 40 anti-human immunodeficiency virus (HIV)-negative patients (15 HBeAg positive, 15 anti-HBe positive an...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(90)90050-2
更新日期:1990-03-01 00:00:00
abstract::Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome. Peginterferon/ribavirin t...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2011.08.006
更新日期:2012-02-01 00:00:00
abstract:BACKGROUND/AIMS:The liver is the main source of circulating insulin-like growth factor binding proteins. In man, the cellular origin of insulin-like growth factor binding proteins has remained obscure. METHODS:Human hepatocytes isolated from surgical specimens were purified and cultured using a collagen gel immobiliza...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(95)80201-0
更新日期:1995-10-01 00:00:00
abstract::In this Grand Round presentation, the case of a man with decompensated liver disease is described. He subsequently developed a fatal pulmonary embolism, which may not have occurred if he had been prescribed prophylactic anticoagulation to prevent venous thromboembolic disease. The burden of thrombotic disease in those...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2017.01.006
更新日期:2017-06-01 00:00:00
abstract:BACKGROUND/AIMS:Herpes simplex virus (HSV) is known to induce fulminant hepatic failure. The aim of this study is to clarify the molecular basis of liver injury in HSV-induced hepatitis. METHODS:Immunocompetent mice were inoculated with HSV or ultraviolet-inactivated HSV (UV-HSV) intravenously. Extent of liver injury ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(03)00385-4
更新日期:2003-11-01 00:00:00
abstract::Data derived from population, case-control, and cohort studies conducted in several Euro-Mediterranean and African countries disclose impressive similarities in the age and modes of hepatitis B virus (HBV) transmission and in the prevalence, duration, and outcome of the four phases of the natural history of chronic in...
journal_title:Journal of hepatology
pub_type: 历史文章,杂志文章,评审
doi:10.1016/j.jhep.2010.12.030
更新日期:2011-07-01 00:00:00
abstract:BACKGROUND & AIMS:Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled s...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2019.12.010
更新日期:2020-05-01 00:00:00
abstract:BACKGROUND/AIMS:Primary sclerosing cholangitis (PSC) is associated with a high risk of cholangiocarcinoma. Our aim was to evaluate the diagnostic value of trypsinogen-1, trypsinogen-2, tumour-associated trypsin inhibitor, human chorionic gonadotropin beta and trypsin-2-alpha(1)-antitrypsin for cholangiocarcinoma and to...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2007.05.017
更新日期:2007-11-01 00:00:00
abstract:BACKGROUND/AIMS:The x gene of hepatitis B virus encodes a transactivating factor of 154 amino acids, termed HBx, which stimulates transcription of multiple viral and cellular genes. The transactivating function is probably associated with a tumorigenic potential of HBx, since x gene sequences, encoding functional HBx, ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(95)80311-4
更新日期:1995-07-01 00:00:00
abstract::Linoleic and alpha-linolenic acids are the fatty acids designated as "essential" since they are not synthesized by mammalian cells and must be provided in the diet. The recent dietary shift towards the consumption of n-6 (omega-6) at the expense of n-3 (omega-3) polyunsaturated fatty acids (PUFAs) is thought to be a p...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2007.08.005
更新日期:2007-11-01 00:00:00
abstract::The ischemic biliary phenotype of hereditary hemorrhagic telangiectasia (HHT) is rare but distinct, with progressive biliary tree ischemia usually resulting in an irreversible secondary sclerosing cholangiopathy. When clinically severe, liver transplant is often indicated. We report three patients with marked HHT asso...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2013.02.006
更新日期:2013-07-01 00:00:00