Complement 5 Inhibition Ameliorates Hepatic Ischemia/reperfusion Injury in Mice, Dominantly via the C5a-mediated Cascade

Abstract

Background. Hepatic ischemia/reperfusion injury (IRI) is a serious complication in liver surgeries, including transplantation. Complement activation seems to be closely involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Complement 5 (C5)-targeted regulation in hepatic IRI. Methods. C5-knockout (B10D2/oSn) and their corresponding wild-type mice (WT, B10D2/nSn) were exposed to 90-minute partial (70%) hepatic ischemia/reperfusion with either anti-mouse-C5 monoclonal antibody (BB5.1) or corresponding control immunoglobulin administration 30 minutes before ischemia. C5a receptor 1 antagonist was also given to WT to identify which cascade, C5a or C5b-9, is dominant. Results. C5-knockout and anti-C5-Ab administration to WT both significantly reduced serum transaminase release and histopathological damages from 2 hours after reperfusion. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and decreased high-mobility group box 1 release. After 6 hours of reperfusion, the infiltration of CD11+ and Ly6-G+ cells, cytokine/chemokine expression, single-stranded DNA+ cells, and cleaved caspase-3 expression were all significantly alleviated by anti-C5-Ab. C5a receptor 1 antagonist was as effective as anti-C5-Ab for reducing transaminases. Conclusions. Anti-C5 antibody significantly ameliorated hepatic IRI, predominantly via the C5a-mediated cascade, not only by inhibiting platelet aggregation during the early phase but also by attenuating the activation of infiltrating macrophages/neutrophils and hepatocyte apoptosis in the late phase of reperfusion. Given its efficacy, clinical availability, and controllability, C5-targeted intervention may provide a novel therapeutic strategy against hepatic IRI.

The liver in sepsis: molecular mechanism of liver failure and their potential for clinical translation

“…There is also a potential benefit of blocking complement response by directly antagonizing C5a receptor 1 (C5AR1) (Sommerfeld et al 2021 ). Investigations in a murine model of sepsis revealed evidence for improved outcomes in C5AR1 deficient mice by reduced pathogen load and mostly preserved liver function (Sommerfeld et al 2021 ; Kusakabe et al 2020 ). A current phase 2 trial with a novel monoclonal Anti-C5a antibody Vilobelimab promises beneficial effects on C5a neutralization.…”

Normothermic regional perfusion in liver transplantation from donation after cardiocirculatory death: Technical, biochemical, and regulatory aspects and review of literature

“…In published protocols, 44,45,47–52 they are measured immediately before starting NRP, after 1 h, and at the end of reconditioning. More frequent measurements are also reported 19–53 . Barcelona's team 44,45 adopted a threshold based on a maximum of three times the upper limit of normality at baseline and of four times at the end of NRP.…”

Complement-targeting therapeutics for ischemia-reperfusion injury in transplantation and the potential for ex vivo delivery

“…targeted C5 with anti-C5 monoclonal antibody or C5aR1 antagonist in a murine model. Both approaches resulted in decreased platelet aggregation in hepatic microcirculation, expression of markers of apoptosis and necrosis, and ROS generation compared to controls ( 80 ). Another C5aR antagonist molecule trialed by Arumugam et al.—the same antagonist used in this group’s renal IRI study—ameliorated hepatic IRI in both a total and partial hepatic ischemia rat model ( 81 ).…”