Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms

Abstract

Liver disease causing end organ failure is a growing cause of mortality. In most cases, the only therapy is liver transplantation. However, liver transplantation is a complex undertaking and its success is dependent on a number of factors. In particular, liver transplantation is subject to the risks of ischaemia‐reperfusion injury (IRI). Liver IRI has significant effects on the function of a liver after transplantation. The cellular and molecular mechanisms governing IRI in liver transplantation are numerous. They involve multiple cells types such as liver sinusoidal endothelial cells, hepatocytes, Kupffer cells, neutrophils and platelets acting via an interconnected network of molecular pathways such as activation of toll‐like receptor signalling, alterations in micro‐RNA expression, production of ROS, regulation of autophagy and activation of hypoxia‐inducible factors. Interestingly, the cellular and molecular events in liver IRI can be correlated with clinical risk factors for IRI in liver transplantation such as donor organ steatosis, ischaemic times, donor age, and donor and recipient coagulopathy. Thus, understanding the relationship of the clinical risk factors for liver IRI to the cellular and molecular mechanisms that govern it is critical to higher levels of success after liver transplantation. This in turn will help in the discovery of therapeutics for IRI in liver transplantation – a process that will lead to improved outcomes for patients suffering from end‐stage liver disease.

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…Liver transplantation is often the sole treatment for end‐stage liver diseases, such as liver cirrhosis, late‐stage PSC and PBC, and liver cancers. However, liver transplantation has a risk of ischemia‐reperfusion injury (IRI), which is characterized by oxidative stress, inflammation, and liver damage, and IRI may lead to graft rejection . A previous study monitored blood pressure of 107 liver transplant recipients and found that approximately 90% of patients had arterial hypertension and abnormal circadian blood pressure pattern after operation .…”

“…However, liver transplantation has a risk of ischemia-reperfusion injury (IRI), which is characterized by oxidative stress, inflammation, and liver damage, and IRI may lead to graft rejection. 97 A previous study monitored blood pressure of 107 liver transplant recipients and found that approximately 90% of patients had arterial hypertension and abnormal circadian blood pressure pattern after operation. 98 Another study analyzed 147 patients who underwent liver transplantation in one institution and found that 45 patients who had transplantation at night suffered higher incidence of intraoperative blood loss and other complications, postoperative abdominal infection, longer operation time, and longer time to restore liver functions after transplantation compared to 102 patients with daytime operation.…”

Biomarkers of Liver Injury during Transplantation in an Era of Machine Perfusion

“…The traditionally accepted model of liver IRI involves a period of cold IRI whilst the donor liver is being procured, followed by a period of warm IRI during the implantation phase of transplantation [10]. It is important to note that much of the basic and translational research performed in this area has involved models of warm IRI, predominantly in small animal experiments [11].…”

“…It is important to note that much of the basic and translational research performed in this area has involved models of warm IRI, predominantly in small animal experiments [11]. This difference has important implications for biomarker discovery, validation and utility, which is further compounded by the fact that cold and warm IRI most likely have variable effects in different types of donor livers [10]. The IRI encompasses a very complex and broad-based injury that still remains to be completely understood, and it should be considered and assessed within the context of the triggering insult and the type of graft exposed to the injury.…”

“…The mechanisms are, however, more complex and involve other processes such as autophagy [16], toll-like receptors [17], hypoxia-inducible factor 1 signalling pathways [18] and other cell types, such as hepatic stellate cells and natural killer cells. The liver IRI have been recently reviewed by Dar et al [10].…”