title: Characterisation of temporal microglia and astrocyte immune responses in bile duct-ligated rat models of cirrhosis.
abstract: OBJECTIVE
  Microglia and astrocyte related pro-inflammatory responses are thought to underpin cerebral sequelae of acute liver failure. Conversely, despite background pro-inflammatory responses in cirrhosis, overt brain swelling and coma associated with acute-on-chronic liver failure, is infrequent unless precipitated (e.g. sepsis). Moreover in other chronic neurodegenerative disorders and sepsis, the brain is protected from recurrent microbial insults by compensatory microglial-associated immune responses. To characterise longitudinal cerebral immune responses in a bile duct-ligated (BDL) rat model of cirrhosis.
  
  
  METHODS
  Rats underwent BDL or sham operation before sacrifice at either 1-day, 1, 2 and 4 weeks post-surgery. We analysed consciousness, brain water, biochemistry and immunohistochemistry to assess activation of microglia (ED-1, OX6 and Iba-1), astrocytes (Glial fibrillary acidic protein - GFAP), cellular stress (Heat shock protein - Hsp 25) and pro-inflammatory mediator expression (inducible nitric oxide synthase (iNOS), interleukin-1beta (IL-1β) and tumour growth factor-beta (TGF-β)).
  
  
  RESULTS
  BDL significantly increased ammonia and bilirubin (P < 0.01 respectively). The classical microglial markers OX6, ED1 and Iba-1 and pro-inflammatory IL-1β and iNOS were not significantly increased. However, the alternative microglial marker and regulatory cytokine TGF-β was elevated from day 1 to 4 weeks post-BDL. GFAP expression was significantly increased in corpus callosum in all groups. In BDL rats, Hsp 25 was also increased in the corpus callosum, peaking at 2 weeks.
  
  
  CONCLUSIONS
  BDL triggers early alternative, but not classical, microglial activation. There was a correlation between astrocyte activation and cellular stress. These findings indicate early cerebral immune responses, which may be associated with immune tolerance to further challenge.
authors: Institute of Hepatology, University College London, Royal Free Hospital London, London, UK.
authors: Gavin A K
authors: GA
authors: Wright
authors: Yalda
authors: Y
authors: Sharifi
authors: Tracy A
authors: TA
authors: Newman
authors: Nathan
authors: N
authors: Davies
authors: Balasubramaniyam
authors: B
authors: Vairappan
authors: Hugh V
authors: HV
authors: Perry
authors: Rajiv
authors: R
authors: Jalan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism*; D001921:Brain / Q000276:immunology / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D056805:Consciousness Monitors; D003337:Corpus Callosum / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000276:immunology*; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C100745:Aif1 protein, rat; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D055551:HSP27 Heat-Shock Proteins; C486114:Hspb1 protein, rat; D053583:Interleukin-1beta; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: ammonia; cerebral haemodynamics; cerebral oedema; cytokines and astrocyte; hepatic encephalopathy; inflammation