title: Sustained Isoprostane E2 Elevation, Inflammation and Fibrosis after Acute Ischaemia-Reperfusion Injury Are Reduced by Pregnane X Receptor Activation.
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-16α-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.
authors: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom.
authors: Aimen O
authors: AO
authors: Amer
authors: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom.
authors: Philip M
authors: PM
authors: Probert
authors: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom; Medical Toxicology Centre, Newcastle University, Newcastle, United Kingdom.
authors: Michael
authors: M
authors: Dunn
authors: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom; Medical Toxicology Centre, Newcastle University, Newcastle, United Kingdom.
authors: Margaret
authors: M
authors: Knight
authors: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom.
authors: Abigail E
authors: AE
authors: Vallance
authors: Comparative Biology Centre, Newcastle University, Newcastle, United Kingdom.
authors: Paul A
authors: PA
authors: Flecknell
authors: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom.
authors: Fiona
authors: F
authors: Oakley
authors: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom; Department of Pathology, Altnagelvin Hospital, Londonderry, United Kingdom.
authors: Iain
authors: I
authors: Cameron
authors: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom.
authors: Steven A
authors: SA
authors: White
authors: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom; Medical Toxicology Centre, Newcastle University, Newcastle, United Kingdom.
authors: Peter G
authors: PG
authors: Blain
authors: Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom.
authors: Matthew C
authors: MC
authors: Wright
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002779:Cholestasis / Q000139:chemically induced / Q000503:physiopathology*; D003250:Constriction; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D028421:Isoprostanes / Q000096:biosynthesis* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000008:administration & dosage; D051381:Rats; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000378:metabolism; D015427:Reperfusion Injury / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology
chemical_list: D028421:Isoprostanes; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D011285:Pregnenolone Carbonitrile