Lipopolysaccharide precipitates hepatic encephalopathy and increases blood–brain barrier permeability in mice with acute liver failure

Chastre, Anne; Bélanger, Marcel; Nguyen, Bich; Butterworth, Roger F.

doi:10.1111/liv.12252

Cited by 54 publications

(34 citation statements)

References 42 publications

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“…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.…”

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confidence: 85%

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Butterworth

2015

Journal of Clinical and Experimental Hepatology

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117

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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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confidence: 85%

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Butterworth

2015

Journal of Clinical and Experimental Hepatology

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117

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“…37 Conversely, others have shown that mice injected with AOM alone do not have increased BBB breakdown alone, but require a priming dose of lipopolysaccharide for the BBB permeability to be evident. 39 Together, these in vivo reports do not support the idea that AOM is directly causing leakiness of the BBB; rather, it is a consequence of liver failure and the resulting complications that arise.…”

Section: The Aom Model Of Acute Liver Failure Is a Valid Model Of Hementioning

confidence: 96%

Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure

McMillin

Frampton

Quinn

et al. 2016

The American Journal of Pathology

115

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“…A number of substances such as ammonia, serotonin, bradykinin, adenosine, purine nucleotides, interleukins, free radicals, nitric oxide, and steroids may influence the brain endothelium function and tightness of the BBB [38]. Inflammation-related BBB permeability changes in acute liver failure [39]. Hepatitis C virus (HCV)-related neurocognitive dysfunction has been believed to be a consequence of cirrhosis-associated hepatic encephalopathy.…”

Section: Discussionmentioning

confidence: 99%

The Inactivation of JAK2/STAT3 Signaling and Desensitization of M1 mAChR in Minimal Hepatic Encephalopathy (MHE) and the Protection of Naringin Against MHE

Ding

Yang

et al. 2014

Cell Physiol Biochem

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Background: We previously reported that elevation of intracranial dopamine (DA) levels from cirrhotic livers is implicated in the pathogenesis of minimal hepatic encephalopathy (MHE). Intracellular events in neurons, which lead to memory loss in MHE by elevated DA, however, remain elusive. Methods: In our present study, an MHE rat model, a DA - intracerebroventricularly (i.c.v.) injected rat model and DA-treated primary cortical neurons (PCNs) were used to study this issue using behavioral tests, double-labeled fluorescent staining, immunoblotting, and semi-quantitative RT-PCR. Results: Cognitive impairment was observed in MHE rats and DA (10 µg, i.c.v.)-treated rats. The levels of DA in the cerebral cortex of both MHE and DA (10 µg)-treated rats were increased. DA conversely modulated the p-JAK2/p-STAT3 levels in PCNs. In accordance, DA downregulated an anacetylcholine-producing enzyme, choline acetyltransferase (ChAT), and desensitized the M1-type muscarinic acetylcholine receptor (M1 mAChR). Furthermore, naringin completely restored cognitive function in MHE/DA (10 µg)-treated models by activating the JAK2/STAT3 axis, paralleling the upregulation of ChAT and sensitization of M1 mAChR. Conclusions: We propose a hypothesis accounting for memory impairment related to MHE: DA-dependent inactivation of the JAK2/STAT3 axis causes memory loss through cholinergic dysfunction. Our findings provide not only a novel pathological hallmark in MHE but also a novel target in MHE therapy.

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Lipopolysaccharide precipitates hepatic encephalopathy and increases blood–brain barrier permeability in mice with acute liver failure

Abstract: These findings represent the first direct evidence of inflammation-related BBB permeability changes in ALF.

Cited by 54 publications

References 42 publications

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure

The Inactivation of JAK2/STAT3 Signaling and Desensitization of M1 mAChR in Minimal Hepatic Encephalopathy (MHE) and the Protection of Naringin Against MHE

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