Insights into the development of peri-biliary fibrosis following hepatic ischaemia-reperfusion injury and the ameliorating effect of PXR activation

Abstract

Despite progress in liver transplantation, biliary complications such as nonanastomotic biliary strictures (NABS) remain its “Achilles heel” and our understanding of the pathogenesis of these lesions remains limited. An inflammatory process following reperfusion injury of the liver is a possible cause for this pathology. The pregnane X receptor (PXR) has gained interest in recent years as a potential therapeutic target for inflammatory bowel and liver conditions. Its role in ischaemia reperfusion injury (IRI) following liver transplantation remains unexplored. The aim of this project was to investigate the development of biliary pathology following ischaemia reperfusion injury and the potential beneficial effect of PXR activation on these lesions. In vitro studies on the pro-fibrotic effect of varying oxygen conditions on human biliary epithelial cells were carried out initially, followed by an in vivo rat model of hepatic ischaemia reperfusion injury to sequentially examine the progression of fibrosis following hepatic IRI and the potential ameliorating effect of PXR activation on this. The project culminates in a retrospective clinical study to confirm the benefit of PXR activation in a cohort of liver transplant recipients The in vitro studies highlighted an active pro-inflammatory role for biliary epithelial cells when subjected to oxygen after a period of hypoxia. Moreover, hepatic IRI was found to cause persistent inflammatory and fibrotic changes beyond the initial ischaemic insult in the in vivo rat model. Activation of the PXR led to a reduction in post-IRI cellular damage, inflammation and fibrosis in the animal model and these promising findings were supported in the clinical study which highlighted a beneficial role for PXR activation in reducing anastomotic biliary strictures and ultimately improving patient survival following liver transplantation This project provides further insight into the pathogenesis of biliary lesions following reperfusion injury and shed further light on the potential role for PXR activation in improving graft outcomes following liver transplantation. It also opens the door for novel therapies such as the use of PXR activators in perfusion fluid, potentially optimising the organ donation pool.