Ischaemia-reperfusion injury in liver transplantation--from bench to bedside

Abstract

Ischaemia-reperfusion injury (IRI) in the liver, a major complication of haemorrhagic shock, resection and transplantation, is a dynamic process that involves the two interrelated phases of local ischaemic insult and inflammation-mediated reperfusion injury. This Review highlights the latest mechanistic insights into innate-adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischaemia-reperfusion, discusses progress in large animal experiments and examines efforts to minimize liver IRI in patients who have received a liver transplant. The interlinked signalling pathways in multiple hepatic cell types, the IRI kinetics and positive versus negative regulatory loops at the innate-adaptive immune interface are discussed. The current gaps in our knowledge and the pathophysiology aspects of IRI in which basic and translational research is still required are stressed. An improved appreciation of cellular immune events that trigger and sustain local inflammatory responses, which are ultimately responsible for organ injury, is fundamental to developing innovative strategies for treating patients who have received a liver transplant and developed ischaemia-reperfusion inflammation and organ dysfunction.

Figure 1

The distinct stages of liver ischaemia–reperfusion injury. Ischaemic injury, a localized process of hepatic metabolic disturbances, results from glycogen consumption, lack of oxygen supply and ATP depletion. The cell-death-released DAMPs, activation of complement (a group of proteins that are involved in tissue injury and/or repair) induced by tissue injury and mitochondrial ROS production triggered by oxygenation all contribute to liver immune activation after reperfusion, which involves multiple liver nonparenchymal cell types, including Kupffer cells, dendritic cells, T cells, NK cells and neutrophils (PMNs). The ischaemia–reperfusion-activated proinflammatory immune cascade sustains itself by recruiting peripheral immune cells from the circulation, and is responsible for the ultimate liver reperfusion injury. Abbreviations: DAMPs, danger-associated molecular patterns; DC, dendritic cells; KC, Kupffer cells; NK, natural killer cell; PMN, polymorphonuclear cells; ROS, reactive oxygen species.

Figure 2

A scheme of liver immune activation against ischaemia–reperfusion injury. The ischaemic insult induces initial cell death, which results in diverse ‘danger’ molecules, such as HMGB1, DNA fragments and histones activating TLR4, RAGE and TLR9 signalling on Kupffer cells and/or dendritic cells and neutrophils. T cells, particularly CD4⁺ T_H1 effectors, might also facilitate and regulate local innate immune activation via CD154–CD40, TIM-1–TIM-3, TIM-4–galectin 9 and PD-L1 pathways. In addition, CD1d-mediated NKT and CD39-mediated NK cell activation contribute to hepatic immune activation against ischaemia–reperfusion. IFN-γ produced by activated NK cells promotes Kupffer cell and/or dendritic cell activation. The proinflammatory milieu, composed of TNF, IL-1β, IL-6, IL-12, CXCL10, CCL2, CXCL8 and ROS, further activates local immune cells and recruits circulating immune cells, culminating in inflammatory reperfusion injury. Abbreviations: HMGB1, high-mobility group protein B1; IFNGR, IFN-γ receptor; iTCR, invariant T cell receptor; NK, natural killer cell; NKT, natural killer T cell; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; PMN, polymorphonuclear cell; RAGE, receptor for advanced glycation end products; STAT4, signal of transducer and activator of transcription 4; T_H1, T-helper type 1 cell; TIM, T cell, immunoglobulin, mucin-containing molecules; TLR, Toll-like receptor.

Figure 3

Regulated hepatic reperfusion and splenojugular venovenous bypass circuits. An extracorporeal centrifugal pump recirculates the animal’s splanchnic venous blood to the heart through a splenojugular venovenous bypass (the direction of the blood flow is indicated by white arrows) to avoid congestion of the splanchnic circulation during total portal occlusion. During regulated hepatic reperfusion, an amount of the animal’s splanchnic venous blood is diverted through a Y-connector from the centrifugal pump and mixed with hepatic perfusion solution in a 4:1 dilution ratio (perfusate). Another extracorporeal roller pump recirculates the perfusate through a paediatric oxygenator heat exchanger and leukoreduction filter before perfusion of the liver through the portal vein (the direction of the perfusate flow is indicated by black arrows). The roller pump regulates the reperfusion pressure (8–12 mmHg) and the oxygenator heat exchanger maintains the perfusate oxygen saturation (to 100%) and temperature (30–32 °C). Permission obtained from Elsevier Ltd © Hong, J. C. et al. Am. J. Coll. Surg. 214, 505–515 (2012).