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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 FlecknellORCiD, Professor Fiona OakleyORCiD, Steven White, Professor Peter Blain, Professor Matthew Wright



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


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


DOI: 10.1371/journal.pone.0136173


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