Enhanced Tumour Necrosis Factor and Interleukin-1 in Fulminant Hepatic Failure

Muto, Yasutoshi; Meager, Anthony; Nouri‐Aria, Kayhan T.; Alexander, G.; Eddleston, AdrianL.W.F.; Williams, Roger

doi:10.1016/s0140-6736(88)90006-2

Cited by 265 publications

(141 citation statements)

References 13 publications

Supporting

Mentioning

137

Contrasting

Order By: Relevance

“…The molecular mechanism for DEX-dependent hepatic cFLIP expression is currently under investigation. The extensive hepatocellular injury of fulminant hepatic failure is thought to be mediated, in part, by ligation of death receptors with their ligands including TNF-a 40 and FasL. 41 TNF-a and Jo2 (anti-Fas antibody) induce hepatic apoptosis, which is considered an important cause for a variety of liver diseases such as viral hepatitis, cholestasis, and ischemic or septic liver injury.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Namkoong

et al. 2005

Cell Death Differ

View full text Add to dashboard Cite

Dexamethasone (DEX) pretreatment protected hepatocytes from TNF-a plus actinomycin D (ActD)-induced apoptosis by suppressing caspase-8 activation and the mitochondriadependent apoptosis pathway. DEX treatment upregulated cellular FLICE inhibitory protein (cFLIP) expression, but did not alter the protein levels of Bcl-2, Bcl-xL, Mcl-1, and cIAP as well as Akt activation. The increased cFLIP mRNA level by DEX was inhibited by ActD, indicating that DEX upregulates cFLIP expression at the transcriptional step. DEX also inhibited Jo2-mediated hepatocyte apoptosis by blocking the formation of the death-inducing signaling complex and caspase-8 activation. Specific downregulation of cFLIP expression using siRNA reversed the antiapoptotic effect of DEX by increasing caspase-8 activation. Moreover, DEX administration into mice increased cFLIP expression in the liver and prevented Jo2-induced hepatic injury by inhibiting caspase-8 and -3 activities. Our results indicate that DEX exerts a protective role in death receptor-induced in vitro and in vivo hepatocyte apoptosis by upregulating cFLIP expression.

show abstract

Section: Discussionmentioning

confidence: 99%

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Namkoong

et al. 2005

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…[6][7][8] Moreover, the existence of SIRS, whether or not it is triggered by infection, is implicated in the progression of encephalopathy and poor outcome in this patient cohort. 6,8 Increased serum levels of proinflammatory cyto-kines (IL-1, IL-6, IL-8, and TNF-␣) are thought to reflect the severity of the inflammatory response evoked in ALF, 7,[9][10][11][12][13][14][15] with some studies reporting higher IL-6 and TNF-␣ levels in nonsurviving ALF patients. 7,10,14,15 Monocytes are central to SIRS secreting large quantities of proinflammatory cytokines and being responsible for antigen presentation through the surface expression of the HLA class II molecule.…”

Section: S Ystemic Inflammatory Response Syndrome (Sirs) Ismentioning

confidence: 99%

Reduced monocyte HLA-DR expression: A novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure

et al. 2006

View full text Add to dashboard Cite

Acute liver failure (ALF) shares striking similarities with septic shock where a decrease in HLA-DR expression on monocytes is associated with disease severity and predicts outcome. We investigated monocyte HLA-DR expression in ALF in relation to inflammatory mediator levels and clinical outcome. Monocyte HLA-DR expression was determined in 50 patients with acetaminophen-induced ALF (AALF) and 20 non-acetaminophen-induced ALF (NAALF). AALF patients were divided into dead/transplanted (AALF-NS, n ‫؍‬ 26) and spontaneous survivors (AALF-S, n ‫؍‬ 24). Fifty patients with chronic liver disease (CLD) and 50 healthy volunteers served as controls. Monocyte HLA-DR expression was determined by double-color flow-cytometry with monoclonal antibodies detecting HLA-DR and monocyte specific CD14. Serum levels of interleukin (IL) -4, -6, -10, tumor necrosis factor (TNF)-␣ and interferon (IFN)-␥ were concomitantly measured by ELISA. Compared to healthy volunteers (75%) and CLD (67%) monocyte HLA-DR percentage expression was lower in AALF (15%, P < .001) and NAALF (22 %, P < .001). Compared to AALF-S, AALF-NS had lower monocyte HLA-DR % (11% vs. 36%, P < .001) and higher levels of IL-4, IL-6, IL-10 and TNF-␣ (P < .001). HLA-DR percentage negatively correlated with INR, blood lactate, pH and levels of encephalopathy (r ‫؍‬ ؊0.8 to ؊0.5, P < .01), IL-10 (r ‫؍‬ ؊0.8, P < .0001), TNF-␣ (r ‫؍‬ ؊0.4, P ‫؍‬ .02). HLA-DR percentage level <15% has a 96% sensitivity and 100% specificity and 98% accuracy in predicting poor prognosis. In conclusion, the strong relationship of monocyte HLA-DR expression with indices of disease severity, mediators of inflammation and outcome indicates a key role for this molecule as a biomarker of disease severity and prognosis. (HEPATOLOGY 2006;44:34-43.)

show abstract

“…[1][2][3] Multiorgan dysfunction in ALF is believed to derive from oxidative stress due to reactive oxygen species and reactive nitrogen species 4 and from immunological injury mediated by cytokines. [5][6][7][8] N-acetylcysteine (NAC) is a thiol-containing agent that scavenges free oxygen radicals and replenishes cellular mitochondrial and cytosolic glutathione stores. [9][10][11] NAC has also been shown to directly scavenge reactive oxygen species and reactive nitrogen species.…”

Section: See Editorial On Pagementioning

confidence: 99%

Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure

et al. 2007

View full text Add to dashboard Cite

Acute liver failure (ALF) carries a high mortality in children. N-acetylcysteine (NAC), an antioxidant agent that replenishes mitochondrial and cytosolic glutathione stores, has been used in the treatment of late acetaminophen-induced ALF and non-acetaminophen-induced ALF. In our unit, NAC was introduced as additional treatment for non-acetaminophen-induced ALF in 1995. The aim of this study was to evaluate the safety and efficacy of NAC in children with ALF not caused by acetaminophen poisoning. A retrospective review of medical records of 170 children presenting with nonacetaminopheninduced ALF between 1989 and 2004 was undertaken. ALF was defined as either international normalized ratio of prothrombin time (INR) Ͼ 2 and abnormal liver function or INR Ͼ1.5 with encephalopathy and abnormal liver function. Children were divided into the following groups: Group 1 (1989)(1990)(1991)(1992)(1993)(1994), standard care (n ϭ 59; 34 [58%] male; median age 2.03 yr, range 0.003-15.8 yr); and Group 2 (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004), standard care and NAC administration (n ϭ 111; 57 [51%] male; median age 3.51 yr, range 0.005-17.4 yr). NAC was administered as a continuous infusion (100 mg/kg/24 hours) until INR Ͻ 1.4, death, or liver transplantation (LT). The median duration of NAC administration in Group 2 was 5 (range, 1-77) days. Complications were noted in 8 (10.8%) children: rash in 3, arrhythmia in 3, and dizziness and peripheral edema in 1. One child had an allergic reaction (bronchospasm) and NAC was stopped. A total of 41 (71%) children in Group 1 vs. 85 (77%) in Group 2 required admission to intensive care, P ϭ not significant (ns). The length of intensive care stay was 6 (range, 1-58) days in Group 1 vs. 5 (range, 1-68) days in Group 2, P ϭ ns and length of hospital stay was 25 (range, 1-264) days vs. 19 (range, 1-201) days, P ϭ 0.05. The 10-yr actuarial survival was 50% in Group 1 compared to 75% in Group 2, P ϭ 0.009. Survival with native liver occurred in 13 (22%) in Group 1 vs. 48 (43%) in Group 2, P ϭ 0.005; 15 (25%) in Group 1 died without transplant vs. 21 (19%) in Group 2, P ϭ ns; and LT was performed in 32 (54%) vs. 42 (38%), P ϭ ns. Death after transplantation occurred in 15 (39%) in Group 1 vs. 8 (16%) in Group 2, P ϭ 0.02. In conclusion, NAC is safe in non-acetaminophen-induced ALF. In this retrospective study NAC was associated with a shorter length of hospital stay, higher incidence of native liver recovery without transplantation, and better survival after transplantation. Liver Transpl 14: [25][26][27][28][29][30] 2008 See Editorial on Page 7Acute liver failure (ALF) in children is a rare but often fatal condition without liver transplantation (LT). [1][2][3] Multiorgan dysfunction in ALF is believed to derive from oxidative stress due to reactive oxygen species and reactive nitrogen species 4 and from immunological injury mediated by cytokines. 5-8 N-acetylcysteine (NAC) is a thiol-containing agent that scavenges free oxygen radicals and replenishes cellular mitochon...

show abstract

Enhanced Tumour Necrosis Factor and Interleukin-1 in Fulminant Hepatic Failure

Cited by 265 publications

References 13 publications

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Reduced monocyte HLA-DR expression: A novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure

Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure

Contact Info

Product

Resources

About