Yalda Sharifi contributed equally as a joint 1st author on this manuscript.
Cirrhosis and Liver Failure
Characterisation of temporal microglia and astrocyte immune responses in bile duct-ligated rat models of cirrhosis
Article first published online: 9 APR 2014
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Volume 34, Issue 8, pages 1184–1191, September 2014
How to Cite
Liver Int. 2014: 34: 1184–1191
Declaration: This paper was presented in an abstract form at the American Association for the Study of Liver meeting, 20011 [Hepatology 2011 Spp. Volume 52, Issue S1 Spp. (Oct 2011) 1644 (DOI: 10.4016/3530.01)]
- Issue published online: 11 AUG 2014
- Article first published online: 9 APR 2014
- Accepted manuscript online: 16 FEB 2014 05:31AM EST
- Manuscript Accepted: 31 JAN 2014
- Manuscript Received: 19 JUN 2013
- cerebral haemodynamics;
- cerebral oedema;
- cytokines and astrocyte;
- hepatic encephalopathy;
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.
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)).
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.
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.