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Sustained Isoprostane E2 Elevation, Inflammation and Fibrosis after Acute Ischaemia-Reperfusion Injury Are Reduced by Pregnane X Receptor Activation

Lookup NU author(s): Aimen Amer, Dr Phillip Probert, Dr Michael Dunn, Margaret Knight, Dr Abigail Vallance, Emeritus Professor Paul Flecknell, Professor Fiona Oakley, Steven White, Professor Peter Blain CBE, Professor Matthew Wright

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Liver grafts donated after cardiac death are increasingly used to expand the donor pool but are prone to ischaemic-type biliary lesions. The anti-inflammatory effects of the activated pregnane X receptor have previously been shown to be beneficial in a number of inflammatory liver conditions. However, its role in reducing peri-portal inflammation and fibrosis following ischaemia-reperfusion injury has not been investigated. Hepatic injury and its response to pregnane X receptor activation was examined after partial hepatic ischaemia-reperfusion injury induced by surgically clamping the left and middle lobar blood vessels in rats. Molecular and pathological changes in the liver were examined over the following 28 days. Ischaemia-reperfusion injury resulted in transient cholestasis associated with microvillar changes in biliary epithelial cell membranes and hepatocellular injury which resolved within days after reperfusion. However, in contrast to chemically-induced acute liver injuries, this was followed by sustained elevation in isoprostane E2, peri-portal inflammation and fibrosis that remained unresolved in the ischaemic reperfused lobe for at least 28 days after clamping. Administration of pregnenolone-16 alpha-carbonitrile-a rodent-specific pregnane X receptor activator-resulted in significant reductions in cholestasis, hepatic injury, ischaemic lobe isoprostane E2 levels, peri-portal inflammation and fibrosis. Hepatic ischaemia-reperfusion injury therefore results in inflammatory and fibrotic changes that persist well beyond the initial ischaemic insult. Drug-mediated activation of the pregnane X receptor reduced these adverse changes in rats, suggesting that the pregnane X receptor is a viable drug target to reduce ischaemic-type biliary lesions in recipients of liver transplants donated after cardiac death.


Publication metadata

Author(s): Amer AO, Probert PM, Dunn M, Knight M, Vallance AE, Flecknell PA, Oakley F, Cameron I, White SA, Blain PG, Wright MC

Publication type: Article

Publication status: Published

Journal: PLoS ONE

Year: 2015

Volume: 10

Issue: 8

Online publication date: 24/08/2015

Acceptance date: 30/07/2015

Date deposited: 02/10/2015

ISSN (electronic): 1932-6203

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pone.0136173

DOI: 10.1371/journal.pone.0136173


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