Characterisation of temporal microglia and astrocyte immune responses in bile duct-ligated rat models of cirrhosis

Liver Int. 2014 Sep;34(8):1184-91. doi: 10.1111/liv.12481. Epub 2014 Apr 9.


Background & aims: 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.

Method: 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.

Conclusion: 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.

Keywords: ammonia; cerebral haemodynamics; cerebral oedema; cytokines and astrocyte; hepatic encephalopathy; inflammation.

MeSH terms

  • Animals
  • Astrocytes / immunology*
  • Biomarkers / metabolism*
  • Brain / immunology
  • Brain / metabolism*
  • Calcium-Binding Proteins / metabolism
  • Consciousness Monitors
  • Corpus Callosum / metabolism
  • Glial Fibrillary Acidic Protein / metabolism
  • HSP27 Heat-Shock Proteins / metabolism
  • Immunohistochemistry
  • Interleukin-1beta / metabolism
  • Liver Cirrhosis, Experimental / immunology*
  • Male
  • Microfilament Proteins / metabolism
  • Microglia / immunology*
  • Nitric Oxide Synthase Type II / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor beta / metabolism


  • Aif1 protein, rat
  • Biomarkers
  • Calcium-Binding Proteins
  • Glial Fibrillary Acidic Protein
  • HSP27 Heat-Shock Proteins
  • Hspb1 protein, rat
  • Interleukin-1beta
  • Microfilament Proteins
  • Transforming Growth Factor beta
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat