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

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.Aim: to characterize 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 challeng