Abstract
The complement system anchors the innate inflammatory response by triggering both cell-mediated and antibody-mediated immune responses against pathogens. The complement system also plays a critical role in sterile tissue injury by responding to damage-associated molecular patterns. The degree and duration of complement activation may be a critical variable controlling the balance between regenerative and destructive inflammation following sterile injury. Recent studies in kidney transplantation suggest that aberrant complement activation may play a significant role in delayed graft function following transplantation, confirming results obtained from rodent models of renal ischemia/reperfusion (I/R) injury. Deactivating the complement cascade through targeting anaphylatoxins (C3a/C5a) might be an effective clinical strategy to dampen reperfusion injury and reduce delayed graft function in liver transplantation. Targeting the complement cascade may be critical in donor livers with mild to moderate steatosis, where elevated lipid burden amplifies stress responses and increases hepatocyte turnover. Steatosis-driven complement activation in the donor liver may also have implications in rejection and thrombolytic complications following transplantation. This review focuses on the roles of complement activation in liver I/R injury, strategies to target complement activation in liver I/R, and potential opportunities to translate these strategies to transplanting donor livers with mild to moderate steatosis.
Highlights
The United Network for Organ Sharing reported 7841 liver transplants performed for end-stage liver disease in 2016 [1]
This review focuses on the role of complement signaling in settings of donor steatosis, the interactions between steatosis and complement activation from procurement through reperfusion
With clinical trials currently underway targeting complement activation in kidney and liver transplantation, this review aims to review the current research on the role of complement activation in non-alcoholic fatty liver disease (NAFLD), liver I/R injury, and aberrant complement signaling in extended criteria donor (ECD) steatosis
Summary
The United Network for Organ Sharing reported 7841 liver transplants performed for end-stage liver disease in 2016 [1]. Increasing the safe utilization of ECD livers will require clarifying the molecular pathways associated with delayed graft function (DGF) or primary non-function (PNF) as well as strategies to quantify and manage these factors without influencing patient outcomes. Obesity is a well-known risk factor for hepatic steatosis, and clinical profiles of waitlist registrants with consistent NAFLD continue to increase [1,11] These trends suggest the prevalence of steatosis will increase in the coming years, and require centers to confidently assess and address donor steatosis or risk a widening gap between transplant candidates and available donor livers. This review focuses on the role of complement signaling in settings of donor steatosis, the interactions between steatosis and complement activation from procurement through reperfusion It addresses the potential for targeting complement activation in ECD steatosis. Sci. 2018, 19, 1750 pathways and molecular mediators driving each phase of liver I/R injury will be summarized followed by a comprehensive review of the complement system in each phase
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