Skip to main content
Erschienen in: Metabolic Brain Disease 2/2013

01.06.2013 | Original Paper

Liver-brain proinflammatory signalling in acute liver failure: Role in the pathogenesis of hepatic encephalopathy and brain edema

verfasst von: Chantal Bémeur, Roger F. Butterworth

Erschienen in: Metabolic Brain Disease | Ausgabe 2/2013

Einloggen, um Zugang zu erhalten

Abstract

A robust neuroinflammatory response characterized by microglial activation and increased brain production of pro-inflammatory cytokines is common in acute liver failure (ALF). Mechanisms proposed to explain the neuroinflammatory response in ALF include direct effects of systemically-derived proinflammatory cytokines and the effects of brain lactate accumulation on pro-inflammatory cytokine release from activated microglia. Cell culture studies reveal a positive synergistic effect of ammonia and pro-inflammatory cytokines on the expression of proteins involved in glutamate homeostasis and in oxidative/nitrosative stress. Proinflammatory cytokines have the capacity to alter blood–brain barrier (BBB) integrity and preliminary studies suggest that the presence of infection in ALF results in rupture of the BBB and vasogenic brain edema. Treatments currently under investigation that are effective in prevention of encephalopathy and brain edema in ALF which are aimed at reduction of neuroinflammation in ALF include mild hypothermia, albumin dialysis systems, N-acetyl cysteine and the antibiotic minocycline with potent anti-inflammatory actions that are distinct from its anti-microbial properties.
Literatur
Zurück zum Zitat Ahboucha S, Gamrani H, Baker G (2012) GABAergic neurosteroids: The “endogenous benzodiazepines” of acute liver failure. Neurochem Int 60(7):707–714PubMedCrossRef Ahboucha S, Gamrani H, Baker G (2012) GABAergic neurosteroids: The “endogenous benzodiazepines” of acute liver failure. Neurochem Int 60(7):707–714PubMedCrossRef
Zurück zum Zitat Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK (2009) Efficacy of L-ornithine L-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterol 136:2159–2168CrossRef Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK (2009) Efficacy of L-ornithine L-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterol 136:2159–2168CrossRef
Zurück zum Zitat Andersson AK, Rönnbäck L, Hansson E (2005) Lactate induces tumour necrosis factor-alpha, interleukin-6 and interleukin-1beta release in microglial- and astroglial-enriched primary cultures. J Neurochem 93:1327–1333PubMedCrossRef Andersson AK, Rönnbäck L, Hansson E (2005) Lactate induces tumour necrosis factor-alpha, interleukin-6 and interleukin-1beta release in microglial- and astroglial-enriched primary cultures. J Neurochem 93:1327–1333PubMedCrossRef
Zurück zum Zitat Bélanger M, Desjardins P, Chatauret N, Butterworth RF (2006) Selectively increased expression of the astrocytic/endothelial glucose transporter protein GLUT1 in acute liver failure. Glia 53(5):557–562PubMedCrossRef Bélanger M, Desjardins P, Chatauret N, Butterworth RF (2006) Selectively increased expression of the astrocytic/endothelial glucose transporter protein GLUT1 in acute liver failure. Glia 53(5):557–562PubMedCrossRef
Zurück zum Zitat Bémeur C, Vaquero J, Desjardins P, Butterworth RF (2007) Protein microarray study reveals toxin-selective cytokine profiles in experimental acute liver failure: beneficial effects of mild hypothermia and N-acetylcysteine. Hepatology 44:611A Bémeur C, Vaquero J, Desjardins P, Butterworth RF (2007) Protein microarray study reveals toxin-selective cytokine profiles in experimental acute liver failure: beneficial effects of mild hypothermia and N-acetylcysteine. Hepatology 44:611A
Zurück zum Zitat Bémeur C, Qu H, Desjardins P, Butterworth RF (2008) IL-1β and TNF-α receptor knockouts delay progression of encephalopathy and brain edema in experimental acute liver failure. Hepatology 48:81A Bémeur C, Qu H, Desjardins P, Butterworth RF (2008) IL-1β and TNF-α receptor knockouts delay progression of encephalopathy and brain edema in experimental acute liver failure. Hepatology 48:81A
Zurück zum Zitat Bémeur C, Chastre A, Desjardins P, Butterworth RF (2010a) No changes in expression of tight junction proteins or blood–brain barrier permeability in azoxymethane-induced experimental acute liver failure. Neurochem Int 56:205–207CrossRef Bémeur C, Chastre A, Desjardins P, Butterworth RF (2010a) No changes in expression of tight junction proteins or blood–brain barrier permeability in azoxymethane-induced experimental acute liver failure. Neurochem Int 56:205–207CrossRef
Zurück zum Zitat Bémeur C, Vaquero J, Desjardins P, Butterworth RF (2010b) N-acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms. Metab Brain Dis 25:241–249PubMedCrossRef Bémeur C, Vaquero J, Desjardins P, Butterworth RF (2010b) N-acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms. Metab Brain Dis 25:241–249PubMedCrossRef
Zurück zum Zitat Bémeur C, Qu H, Desjardins P, Butterworth RF (2010c) IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure. Neurochem Int 56:213–215PubMedCrossRef Bémeur C, Qu H, Desjardins P, Butterworth RF (2010c) IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure. Neurochem Int 56:213–215PubMedCrossRef
Zurück zum Zitat Bernal W, Donaldson P, Underhill J, Wendon J, Williams R (1998) Tumor necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure. J Hepatol 29:53–59PubMedCrossRef Bernal W, Donaldson P, Underhill J, Wendon J, Williams R (1998) Tumor necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure. J Hepatol 29:53–59PubMedCrossRef
Zurück zum Zitat Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J (2007) Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology 46:1844–1852PubMedCrossRef Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J (2007) Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology 46:1844–1852PubMedCrossRef
Zurück zum Zitat Bozza FA, Garteiser P, Oliveira MF, Doblas S, Cranford R, Saunders D, Jones I, Towner RA, Castro-Faria-Neto HC (2010) Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study. J Cereb Blood Flow Metab 30:440–448PubMedCrossRef Bozza FA, Garteiser P, Oliveira MF, Doblas S, Cranford R, Saunders D, Jones I, Towner RA, Castro-Faria-Neto HC (2010) Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study. J Cereb Blood Flow Metab 30:440–448PubMedCrossRef
Zurück zum Zitat Butterworth RF (2011) Hepatic encephalopathy: A central neuroinflammatory disorder? Hepatology 53:1372–1376PubMedCrossRef Butterworth RF (2011) Hepatic encephalopathy: A central neuroinflammatory disorder? Hepatology 53:1372–1376PubMedCrossRef
Zurück zum Zitat Butterworth RF (2012) “Chapter 3: Neuroinflammation in the pathogenesis of hepatic encephalopathy.” In Hepatic Encephalopathy, Mullen KD and Prakash RK (editors), Clinical Gastroenterology: 19–34 Butterworth RF (2012) “Chapter 3: Neuroinflammation in the pathogenesis of hepatic encephalopathy.” In Hepatic Encephalopathy, Mullen KD and Prakash RK (editors), Clinical Gastroenterology: 19–34
Zurück zum Zitat Chastre A, Jiang W, Desjardins P, Butterworth RF (2010) Ammonia and proinflammatory cytokines modify expression of genes coding for astrocytic proteins implicated in brain edema in acute liver failure. Metab Brain Dis 25:17–21PubMedCrossRef Chastre A, Jiang W, Desjardins P, Butterworth RF (2010) Ammonia and proinflammatory cytokines modify expression of genes coding for astrocytic proteins implicated in brain edema in acute liver failure. Metab Brain Dis 25:17–21PubMedCrossRef
Zurück zum Zitat Chastre A, Bélanger M, Butterworth RF (2012a) Modest systemic inflammation precipitates encephalopathy and ruptures the blood–brain barrier in acute liver failure. Hepatology 56:956A Chastre A, Bélanger M, Butterworth RF (2012a) Modest systemic inflammation precipitates encephalopathy and ruptures the blood–brain barrier in acute liver failure. Hepatology 56:956A
Zurück zum Zitat Chastre A, Bélanger M, Beauchesne E, Nguyen BN, Desjardins P, Butterworth RF (2012b) Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liverfailure and its neurological complications. PLoS One 7(11):e49670 Chastre A, Bélanger M, Beauchesne E, Nguyen BN, Desjardins P, Butterworth RF (2012b) Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liverfailure and its neurological complications. PLoS One 7(11):e49670
Zurück zum Zitat Chatauret N, Zwingmann C, Rose C, Leibfritz D, Butterworth RF (2003) Effects of hypothermia on brain glucose metabolism in acute liver failure: a H/C-nuclear magnetic resonance study. Gastroenterol 125:815–824CrossRef Chatauret N, Zwingmann C, Rose C, Leibfritz D, Butterworth RF (2003) Effects of hypothermia on brain glucose metabolism in acute liver failure: a H/C-nuclear magnetic resonance study. Gastroenterol 125:815–824CrossRef
Zurück zum Zitat Chu CJ, Wang SS, Lee FY, Chang FY, Lin HC, Hou MC, Chan CC, Wu SL, Chen CT, Huang HC, Lee SD (2001) Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure. Eur J Clin Invest 31:156–163PubMedCrossRef Chu CJ, Wang SS, Lee FY, Chang FY, Lin HC, Hou MC, Chan CC, Wu SL, Chen CT, Huang HC, Lee SD (2001) Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure. Eur J Clin Invest 31:156–163PubMedCrossRef
Zurück zum Zitat Chung C, Gottstein J, Blei AT (2001) Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 34:249–254PubMedCrossRef Chung C, Gottstein J, Blei AT (2001) Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 34:249–254PubMedCrossRef
Zurück zum Zitat Claudio L, Martiney JA, Brosnan CF (1994) Ultrastructural studies of the blood-retina barrier after exposure to interleukin-1 beta or tumor necrosis factor-alpha. Lab Invest 70(6):850–861PubMed Claudio L, Martiney JA, Brosnan CF (1994) Ultrastructural studies of the blood-retina barrier after exposure to interleukin-1 beta or tumor necrosis factor-alpha. Lab Invest 70(6):850–861PubMed
Zurück zum Zitat Clemmeson JO, Larsen FS, Kondrup J, Hansen BA, Ott P (1999) Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29:648–653CrossRef Clemmeson JO, Larsen FS, Kondrup J, Hansen BA, Ott P (1999) Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29:648–653CrossRef
Zurück zum Zitat Davies DC (2002) Blood–brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 200:639–646PubMedCrossRef Davies DC (2002) Blood–brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 200:639–646PubMedCrossRef
Zurück zum Zitat Deutz NE, Chamuleau RA, de Graaf AA, Bovée WM, de Beer R (1988) In vivo 31P NMR spectroscopy of the rat cerebral cortex during acute hepatic encephalopathy. NMR Biomed 1:101–106PubMedCrossRef Deutz NE, Chamuleau RA, de Graaf AA, Bovée WM, de Beer R (1988) In vivo 31P NMR spectroscopy of the rat cerebral cortex during acute hepatic encephalopathy. NMR Biomed 1:101–106PubMedCrossRef
Zurück zum Zitat de Vries HE, Blom-Roosemalen MC, van Oosten M, de Boer AG, van Berkel TJ, Breimer DD, Kuiper J (1996) The influence of cytokines on the integrity of the blood–brain barrier in vitro. J Neuroimmunol 64:37–43PubMedCrossRef de Vries HE, Blom-Roosemalen MC, van Oosten M, de Boer AG, van Berkel TJ, Breimer DD, Kuiper J (1996) The influence of cytokines on the integrity of the blood–brain barrier in vitro. J Neuroimmunol 64:37–43PubMedCrossRef
Zurück zum Zitat Dixit V, Chang TM (1990) Brain edema and the blood brain barrier in galactosamine-induced fulminant hepatic failure rats. An animal model for evaluation of liver support systems. ASAIO Trans 36(1):21–27PubMed Dixit V, Chang TM (1990) Brain edema and the blood brain barrier in galactosamine-induced fulminant hepatic failure rats. An animal model for evaluation of liver support systems. ASAIO Trans 36(1):21–27PubMed
Zurück zum Zitat Guo LM, Liu JY, Xu DZ, Li BS, Han H, Wang LH, Zhang WY, Lu LH, Guo X, Sun FX, Zhang HY, Liu XD, Zhang JP, Yao Y, He ZP, Wang MM (2003) Application of molecular adsorbents recirculating system to remove NO and cytokines in severe liver failure patients with multiple organ dysfunction syndrome. Liver Int 23:16–20PubMedCrossRef Guo LM, Liu JY, Xu DZ, Li BS, Han H, Wang LH, Zhang WY, Lu LH, Guo X, Sun FX, Zhang HY, Liu XD, Zhang JP, Yao Y, He ZP, Wang MM (2003) Application of molecular adsorbents recirculating system to remove NO and cytokines in severe liver failure patients with multiple organ dysfunction syndrome. Liver Int 23:16–20PubMedCrossRef
Zurück zum Zitat Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Cheridan JF, Godbout JP (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflamm 5:15CrossRef Henry CJ, Huang Y, Wynne A, Hanke M, Himler J, Bailey MT, Cheridan JF, Godbout JP (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflamm 5:15CrossRef
Zurück zum Zitat Jeppsson B, Freund HR, Gimmon Z, James JH, von Meyenfeldt MF, Fischer JE (1981) Blood–brain barrier derangement in sepsis: cause of septic encephalopathy? Am J Surg 14:136–142CrossRef Jeppsson B, Freund HR, Gimmon Z, James JH, von Meyenfeldt MF, Fischer JE (1981) Blood–brain barrier derangement in sepsis: cause of septic encephalopathy? Am J Surg 14:136–142CrossRef
Zurück zum Zitat Jiang W, Qu H, Desjardins P, Chatauret N, Bélanger M, Butterworth RF (2006) Unequivocal evidence for cytokine accumulation in brain in experimental acute liver failure. Hepatology 44:366A Jiang W, Qu H, Desjardins P, Chatauret N, Bélanger M, Butterworth RF (2006) Unequivocal evidence for cytokine accumulation in brain in experimental acute liver failure. Hepatology 44:366A
Zurück zum Zitat Jiang W, Desjardins P, Butterworth RF (2009a) Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia. J Cereb Blood Flow Metab 29:944–9952PubMedCrossRef Jiang W, Desjardins P, Butterworth RF (2009a) Direct evidence for central proinflammatory mechanisms in rats with experimental acute liver failure: protective effect of hypothermia. J Cereb Blood Flow Metab 29:944–9952PubMedCrossRef
Zurück zum Zitat Jiang W, Desjardins P, Butterworth RF (2009b) Molecular basis of synergism between brain ammonia and proinflammatory mechanisms in acute liver failure. Hepatology 50:116A Jiang W, Desjardins P, Butterworth RF (2009b) Molecular basis of synergism between brain ammonia and proinflammatory mechanisms in acute liver failure. Hepatology 50:116A
Zurück zum Zitat Jiang W, Desjardins P, Butterworth RF (2009c) Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline. J Neurochem 109:485–493PubMedCrossRef Jiang W, Desjardins P, Butterworth RF (2009c) Cerebral inflammation contributes to encephalopathy and brain edema in acute liver failure: protective effect of minocycline. J Neurochem 109:485–493PubMedCrossRef
Zurück zum Zitat Kato M, Hughes RD, Keays RT, Williams R (1992) Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology 15:1060–1066PubMedCrossRef Kato M, Hughes RD, Keays RT, Williams R (1992) Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology 15:1060–1066PubMedCrossRef
Zurück zum Zitat Kim KS, Wass CA, Cross AS, Opal SM (1992) Modulation of blood–brain barrier permeability by tumor necrosis factor and antibody to tumor necrosis factor in the rat. Lymphokine Cytokine Res 11:293–298PubMed Kim KS, Wass CA, Cross AS, Opal SM (1992) Modulation of blood–brain barrier permeability by tumor necrosis factor and antibody to tumor necrosis factor in the rat. Lymphokine Cytokine Res 11:293–298PubMed
Zurück zum Zitat Knecht K, Michalak A, Rose C, Rothstein JD, Butterworth RF (1997) Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure. Neurosci Lett 229:201–203PubMedCrossRef Knecht K, Michalak A, Rose C, Rothstein JD, Butterworth RF (1997) Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure. Neurosci Lett 229:201–203PubMedCrossRef
Zurück zum Zitat Lai JC, Cooper AJ (1986) Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors. J Neurochem 47:1376–1386PubMedCrossRef Lai JC, Cooper AJ (1986) Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors. J Neurochem 47:1376–1386PubMedCrossRef
Zurück zum Zitat Livingstone AS, Potvin M, Goresky CA, Finlayson MH, Hinchey EJ (1977) Changes in the blood–brain barrier in hepatic coma after hepatectomy in the rat. Gastroenterol 73:697–704 Livingstone AS, Potvin M, Goresky CA, Finlayson MH, Hinchey EJ (1977) Changes in the blood–brain barrier in hepatic coma after hepatectomy in the rat. Gastroenterol 73:697–704
Zurück zum Zitat Michalak A, Rose C, Butterworth J, Butterworth RF (1996) Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure. Hepatology 24:908–913PubMedCrossRef Michalak A, Rose C, Butterworth J, Butterworth RF (1996) Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure. Hepatology 24:908–913PubMedCrossRef
Zurück zum Zitat Norenberg MD, Huo Z, Neary JT, Roig-Cantesano A (1997) The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: relation to energy metabolism and glutamatergic neurotransmission. Glia 21:124–133PubMedCrossRef Norenberg MD, Huo Z, Neary JT, Roig-Cantesano A (1997) The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: relation to energy metabolism and glutamatergic neurotransmission. Glia 21:124–133PubMedCrossRef
Zurück zum Zitat Odeh M (2007) Pathogenesis of hepatic encephalopathy: the tumour necrosis factor-alpha theory. Eur J Clin Invest 37:291–304PubMedCrossRef Odeh M (2007) Pathogenesis of hepatic encephalopathy: the tumour necrosis factor-alpha theory. Eur J Clin Invest 37:291–304PubMedCrossRef
Zurück zum Zitat Vaquero J, Polson J, Chung C, Helenowski I, Schiodt FV, Reisch J, Lee WM, Blei AT (2003) Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterol 125:755–764CrossRef Vaquero J, Polson J, Chung C, Helenowski I, Schiodt FV, Reisch J, Lee WM, Blei AT (2003) Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterol 125:755–764CrossRef
Zurück zum Zitat Vaquero J (2012) Therapeutic hypothermia in the management of acute liver failure. Neurochem Int 60:723–735PubMedCrossRef Vaquero J (2012) Therapeutic hypothermia in the management of acute liver failure. Neurochem Int 60:723–735PubMedCrossRef
Zurück zum Zitat Wright G, Shawcross D, Olde Damink SW, Jalan R (2007) Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension. Metab Brain Dis 22:375–388PubMedCrossRef Wright G, Shawcross D, Olde Damink SW, Jalan R (2007) Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension. Metab Brain Dis 22:375–388PubMedCrossRef
Zurück zum Zitat Zwingmann C, Chatauret N, Leibfritz D, Butterworth RF (2003) Selective increase of brain lactate synthesis in experimental acute liver failure: results of [H-C] nuclear magnetic resonance study. Hepatology 37:420–428PubMedCrossRef Zwingmann C, Chatauret N, Leibfritz D, Butterworth RF (2003) Selective increase of brain lactate synthesis in experimental acute liver failure: results of [H-C] nuclear magnetic resonance study. Hepatology 37:420–428PubMedCrossRef
Metadaten
Titel
Liver-brain proinflammatory signalling in acute liver failure: Role in the pathogenesis of hepatic encephalopathy and brain edema
verfasst von
Chantal Bémeur
Roger F. Butterworth
Publikationsdatum
01.06.2013
Verlag
Springer US
Erschienen in
Metabolic Brain Disease / Ausgabe 2/2013
Print ISSN: 0885-7490
Elektronische ISSN: 1573-7365
DOI
https://doi.org/10.1007/s11011-012-9361-3

Weitere Artikel der Ausgabe 2/2013

Metabolic Brain Disease 2/2013 Zur Ausgabe

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.