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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., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: In liver failure, inflammation synergistically exacerbates the deleterious cerebral effects of ammonia. The aims were to test whether treatment with the ammonia-lowering agent ornithine phenylacetate (OP) and/or anti-TNF-α (infliximab) prevent the deleterious brain consequences of lipopolysaccharide (LPS) in cirrhotic rats., Design: Rats 4 weeks following bile duct-ligation (BDL), sham-operation (sham) and/or 7 days hyperammonemic feed (HD), were randomized to receive LPS (1 mg/kg) or saline, and treatment with either 3 days intraperitoneal injections of OP (0.6 g/kg) and/or infliximab, 10 mg/kg. Animals were sacrificed at coma stages or at 3 h., Results: In sham rats, both HD and LPS increased brain water, with an increase in ammonia in the former and brain cytokines in the latter but with no effect on consciousness. BDL + HD rats caused significantly higher plasma ammonia, TNF-α and IL-6 levels compared to sham. LPS significantly worsened coma stage, increased brain water and plasma and brain TNF-α. OP significantly delayed LPS-induced progression to coma stages (P < 0.009), reduced arterial ammonia and brain water (P < 0.001 and P < 0.01 respectively), which was associated with a significant reduction in cytokines. Infliximab significantly reduced plasma and brain cytokines, but not brain water. OP + infliximab attenuated increase in brain water and delayed occurrence of coma, which was not different to OP alone. In BDL rats, OP reduced the expression of brain iNOS and NFκB., Conclusion: Reduction in ammonia with OP in cirrhotic rats prevents LPS-induced brain edema and delays coma, suggesting that ammonia may prime the brain to the deleterious effect of LPS, possibly through effects on iNOS and NFκB related mechanisms., (© 2011 John Wiley & Sons A/S.)