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.
Highlights
The growth in liver transplant waiting lists is currently being met with only a modest increase in the number of organ donors and the gap between organ demand and supply continues to widen [1,2]
IRI caused a transient cholestasis in the absence of bile duct occlusion To establish whether an acute IRI could result in pathological changes relevant to those observed in donated after cardiac death (DCD) liver grafts, rats were subjected to IRI, allowed to recover and the liver examined up to 28 days later (Fig 1A, study 1)
The data in this report demonstrate that IRI resulted in marked centrilobular and mid-zonal hepatocellular injury in the early reperfusion period and chronic peri-portal inflammation that persisted for at least 28 days post-reperfusion in the ischaemic lobes, which correlated with specific elevations in isoprostane E2 levels
Summary
The growth in liver transplant waiting lists is currently being met with only a modest increase in the number of organ donors and the gap between organ demand and supply continues to widen [1,2]. Organs donated after cardiac death (DCD) are increasingly being utilised in an attempt to bridge this gap [3] despite a significantly higher risk of biliary complications and graft failure among recipients of these organs compared to those donated after brain death (DBD) [4,5]. Ischaemic-type biliary lesions (ITBL) represent a substantial proportion of complications and are a significant cause of graft failure and death following deceased donor liver transplantation [6,7,8]. In view of the existing organ shortage and the significant risk associated with DCD liver transplantation, it is imperative that all potential strategies for optimising DCD grafts are examined in order to minimise graft loss and insure the best possible outcome for liver transplant recipients
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