Mild Hypothermia Attenuates Liver Injury and Improves Survival in Mice With Acetaminophen Toxicity

Vaquero, Javier; Bélanger, Marcel; James, Laura P.; Herrero, Raquel; Desjardins, Paul; Côté, Jean; Blei, Andrés T.; Butterworth, Roger F.

doi:10.1053/j.gastro.2006.11.025

Cited by 68 publications

(56 citation statements)

References 46 publications

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“…It therefore cannot be ruled out that we missed the presence of apoptotic hepatocytes at a very early stage (less than 3 hours) after treatment. If apoptosis had occurred between the 5-to 24-hour time points investigated in fasted mice and the morphological evidence of apoptosis had been missed (39), K18 cleavage should have been detected at the 24-hour time point, based on the demonstrated long half-life of fragmented K18. Apoptotic hepatocytes, as apoptotic bodies, are rapidly phagocytosed by both hepatocytes and Kupffer cells, but could also be phagocytosed by circulating monocytes, in particular in the liver as an organ with extensive constant blood throughput (38).…”

Section: Discussionmentioning

confidence: 99%

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Antoine

Williams

Kipar

et al. 2010

Mol Med

116

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Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 h can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP . We also investigated in fasted mice the critical role played by inhibition of caspasedependent cysteine 106 oxidation within high mobility group box-1 protein (HMGB1) released by ATP depletion in dying cells as a mechanism of immune activation. In fed mice treated with APAP, necrosis was the dominant form of hepatocyte death. However, apoptosis was also observed, indicated by K18 cleavage, DNA laddering and procaspase-3 processing. In fasted mice treated with APAP, only necrosis was observed. Inflammatory cell recruitment as a consequence of hepatocyte death was observed only in fasted mice treated with APAP or fed mice cotreated with a caspase inhibitor. Hepatic inflammation was also associated with loss in detection of serum oxidized-HMGB1. A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic ATP, which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology.

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Section: Discussionmentioning

confidence: 99%

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Antoine

Williams

Kipar

et al. 2010

Mol Med

116

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“…A dose of 300 mg/kg paracetamol was previously used to investigate the mechanism of paracetamolinduced hypothermia (Ayoub et al, 2004). Although high, this dose is within the pharmacological subtoxic range in mice (Muth-Selbach et al, 1999;Vaquero et al, 2007). In CB 1 R knockout mice, 300 mg/kg paracetamol i.p.…”

Section: Resultsmentioning

confidence: 99%

Paracetamol-Induced Hypothermia Is Independent of Cannabinoids and Transient Receptor Potential Vanilloid-1 and Is Not Mediated by AM404

Ayoub

Pryce²,

Seed³

et al. 2011

Drug Metab Dispos

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ABSTRACT:In recent years, there has been increasing interest in hypothermia induced by paracetamol for therapeutic purposes, which, in some instances, has been reported as a side effect. Understanding the mechanism by which paracetamol induces hypothermia is therefore an important question. In this study, we investigated whether the novel metabolite of paracetamol, N-(4-hydroxyphenyl)arachidonylamide (AM404), which activates the cannabinoid (CB) and transient receptor potential vanilloid-1 (TRPV1) systems, mediates the paracetamolinduced hypothermia. The hypothermic response to 300 mg/kg paracetamol in CB 1 receptor (CB 1 R) and TRPV1 knockout mice was compared to wild-type mice. Hypothermia induced by paracetamol was also investigated in animals pretreated with the CB 1 R or TRPV1 antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperdinyl-1H-pyrazole-3-carboxamide trifluoroacetate salt (AM251) or 4-chloro-3-methoxycinnamanilide (SB366791), respectively. In CB 1 R or TRPV1 knockout mice, paracetamol induced hypothermia to the same extent as in wild-type mice. In addition, in C57BL/6 mice pretreated with AM251 or SB366791, paracetamol induced hypothermia to the same extent as in control mice. AM404 failed to induce hypothermia at pharmacological doses. Inhibition of fatty acid amide hydrolase (FAAH), which is involved in the metabolism of paracetamol to AM404, did not prevent the development of hypothermia with paracetamol. Paracetamol also induced hypothermia in FAAH knockout mice to the same extent as wild-type mice. We conclude that paracetamol induces hypothermia independent of cannabinoids and TRPV1 and that AM404 does not mediate this response. In addition, potential therapeutic value of combinational drug-induced hypothermia is supported by experimental evidence.

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“…Mild hypothermia also possesses antiinflammatory properties; it reduces microglial activation in the brain in experimental ALF 38,43 with concomitant reduction of brain pro-inflammatory cytokines. Hypothermia also reduces the extent of acetaminopheninduced liver injury in mice 57 with the potential to do so in ALF patients. Although mild hypothermia is used in an ad hoc manner as a bridge to transplantation in some tertiary centers, tragically, a lack of clear guidelines precludes its more widespread use in the management of ALF and its complications at this time.…”

Section: Mild Hypothermiamentioning

confidence: 99%

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Butterworth

2015

Journal of Clinical and Experimental Hepatology

Self Cite

113

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Neuropathologic investigations in acute liver failure (ALF) reveal significant alterations to neuroglia consisting of swelling of astrocytes leading to cytotoxic brain edema and intracranial hypertension as well as activation of microglia indicative of a central neuroinflammatory response. Increased arterial ammonia concentrations in patients with ALF are predictors of patients at risk for the development of brain herniation. Molecular and spectroscopic techniques in ALF reveal alterations in expression of an array of genes coding for neuroglial proteins involved in cell volume regulation and mitochondrial function as well as in the transport of neurotransmitter amino acids and in the synthesis of pro-inflammatory cytokines. Liver-brain pro-inflammatory signaling mechanisms involving transduction of systemically-derived cytokines, ammonia neurotoxicity and exposure to increased brain lactate have been proposed. Mild hypothermia and N-Acetyl cysteine have both hepatoprotective and neuro-protective properties in ALF. Potentially effective anti-inflammatory agents aimed at control of encephalopathy and brain edema in ALF include etanercept and the antibiotic minocycline, a potent inhibitor of microglial activation. Translation of these potentially-interesting findings to the clinic is anxiously awaited. ( J CLIN EXP HEPATOL 2015;5:S96-S103) A cute liver failure (ALF), also referred to as fulminant hepatic failure, invariably leads to central nervous system dysfunction that may include encephalopathy, seizures and brain edema, a major cause of intracranial hypertension and brain herniation, a leading cause of mortality in ALF. An increase in cerebral blood flow frequently accompanies the onset of brain edema. 1Neuropathological assessments of the brain in both human and experimental ALF reveals significant changes to neuroglia in general and to astrocytes and microglia, in particular. Astrocytes in brain sections from patients who died in ALF are swollen 2 as are their mitochondria (Figure 1). Based upon these observations, it is generally assumed that the brain edema that accompanies ALF is primarily, if not exclusively, cytotoxic in nature. Studies in experimental animals with ALF due to toxic liver injury show a similar pattern of changes as well as alterations in expression of genes coding for key astrocytic proteins. 3Although gross alterations of the blood-brain barrier (BBB) are not generally a feature of ALF, alterations of cerebrovascular endothelial cell function have occasionally been described. 2,4 On the other hand, material from ALF animals in which edema and encephalopathy were precipitated by infection manifest clear alterations of both BBB function and of expression of BBB tight junction proteins.5 These latter findings suggest that, in ALF accompanied by significant infection/inflammation, brain edema may comprise both cytotoxic and vasogenic components. BRAIN METABOLISM IN ACUTE LIVER FAILUREALF leads to severe compromise of cerebral metabolism and includes increases of cerebral blood flow, decrea...

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Mild Hypothermia Attenuates Liver Injury and Improves Survival in Mice With Acetaminophen Toxicity

Cited by 68 publications

References 46 publications

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

Paracetamol-Induced Hypothermia Is Independent of Cannabinoids and Transient Receptor Potential Vanilloid-1 and Is Not Mediated by AM404

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

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