Abstract
While liver transplantation remains the sole treatment option for patients with end-stage liver disease, there are numerous limitations to liver transplantation including the scarcity of donor livers and a rise in livers that are unsuitable to transplant such as those with excess steatosis. Fatty livers are susceptible to ischaemia-reperfusion (IR) injury during transplantation and IR injury results in primary graft non-function, graft failure and mortality. Recent studies have described new cell death pathways which differ from the traditional apoptotic pathway. Necroptosis, a regulated form of cell death, has been associated with hepatic IR injury. Receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL) are thought to be instrumental in the execution of necroptosis. The study of hepatic necroptosis and potential therapeutic approaches to attenuate IR injury will be a key factor in improving our knowledge regarding liver transplantation with fatty donor livers. In this review, we focus on the effect of hepatic steatosis during liver transplantation as well as molecular mechanisms of necroptosis and its involvement during liver IR injury. We also discuss the immune responses triggered during necroptosis and examine the utility of necroptosis inhibitors as potential therapeutic approaches to alleviate IR injury.
Highlights
Liver transplantation still remains the only curative option for the patients with end-stage liver disease
receptor-interacting protein kinase 1 (RIPK1)/Receptor-interacting protein kinase 3 (RIPK3)/mixed-lineage kinase domain-like pseudokinase (MLKL)-mediated necroptosis played a critical role in rat nucleus pulposus (NP) cell death induced by compression, a mechanical stress [138]
Liver transplantation has been regarded as an only treatment option for patients with end-stage illness and the shortage of donor livers has emphasised the use of extended criteria donor livers, such as steatotic livers to increase liver transplantation rates
Summary
Liver transplantation still remains the only curative option for the patients with end-stage liver disease. Marginal or extended criteria donor livers are defined as an organ with an increased risk of primary non-function (PNF) or delayed graft failure that causes an increased risk of morbidity or mortality in the recipient [4,7]. During retrieval of a DCD liver the organ enters a phase of ischaemia which can trigger the release of stress factors resulting in secretion of endotoxin and gut bacteria into the portal circulation [14]. These endotoxins potentially translocate to the liver during cold perfusion [15]. We discuss the immune responses triggered during necroptosis and examine the use of inhibitors of necroptosis as potential therapeutic approaches to alleviate IR injury
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