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

Characterization of temporal microglia and astrocyte immune responses in bile-duct ligated rat models of cirrhosis
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-1?) and tumour growth factor-beta (TGF-?)).

Results: BDL significantly increased ammonia and bilirubin (p<0.01, respectively). The classical microglial markers OX6, ED1 and Iba-1 and pro-inflammatory IL-1? and iNOS were not significantly increased. However, the alternative microglial marker and regulatory cytokine TGF-? 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
ammonia, cerebral haemodynamics, cerebral oedema, cytokines and astrocyte, hepatic encephalopathy, inflammation
1478-3223
1184-1191
Wright, G.
9cf8d03e-790c-4b94-80aa-708e03544740
Sharifi, Y.
da9f56fd-4425-4e47-b9ff-b76c804d5fd3
Newman, Tracey A.
322290cb-2e9c-445d-a047-00b1bea39a25
Davies, N.A.
8e745499-b738-4618-9af6-7cddda32f951
Vairappan, B.
3a210be8-eb60-4a25-80c4-e945bcc498d1
Perry, V.H.
8f29d36a-8e1f-4082-8700-09483bbaeae4
Jalan, R.
3543765a-df04-4fe0-8534-a5517e7dcf56
Wright, G.
9cf8d03e-790c-4b94-80aa-708e03544740
Sharifi, Y.
da9f56fd-4425-4e47-b9ff-b76c804d5fd3
Newman, Tracey A.
322290cb-2e9c-445d-a047-00b1bea39a25
Davies, N.A.
8e745499-b738-4618-9af6-7cddda32f951
Vairappan, B.
3a210be8-eb60-4a25-80c4-e945bcc498d1
Perry, V.H.
8f29d36a-8e1f-4082-8700-09483bbaeae4
Jalan, R.
3543765a-df04-4fe0-8534-a5517e7dcf56

Wright, G., Sharifi, Y., Newman, Tracey A., Davies, N.A., Vairappan, B., Perry, V.H. and Jalan, R. (2014) Characterization of temporal microglia and astrocyte immune responses in bile-duct ligated rat models of cirrhosis. Liver International, 34 (8), 1184-1191. (doi:10.1111/liv.12481). (PMID:24528887)

Record type: Article

Abstract

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-1?) and tumour growth factor-beta (TGF-?)).

Results: BDL significantly increased ammonia and bilirubin (p<0.01, respectively). The classical microglial markers OX6, ED1 and Iba-1 and pro-inflammatory IL-1? and iNOS were not significantly increased. However, the alternative microglial marker and regulatory cytokine TGF-? 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

Full text not available from this repository.

More information

Submitted date: 19 June 2013
e-pub ahead of print date: 9 April 2014
Published date: September 2014
Keywords: ammonia, cerebral haemodynamics, cerebral oedema, cytokines and astrocyte, hepatic encephalopathy, inflammation
Organisations: Faculty of Medicine, Centre for Biological Sciences

Identifiers

Local EPrints ID: 362733
URI: http://eprints.soton.ac.uk/id/eprint/362733
ISSN: 1478-3223
PURE UUID: 16863d21-5519-4c77-be3f-d867a3db8f78
ORCID for Tracey A. Newman: ORCID iD orcid.org/0000-0002-3727-9258

Catalogue record

Date deposited: 07 Mar 2014 10:03
Last modified: 29 Oct 2019 02:04

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