Research progress on the complement system in ischemia-reperfusion injury of organ transplantation

Abstract

Ischemia-reperfusion injury (IRI) critically affects graft survival following organ transplantation, where complement activation mediates the inflammation, endothelial damage, and adaptive immune responses. This review synthesizes the mechanisms through which the classical, lectin, and alternative complement pathways drive organ-specific IRI pathophysiology by generating anaphylatoxins (C3a/C5a) and membrane attack complexes (C5b-9). Specifically, locally synthesized C3 predominates in renal tubular injury, hepatic C3a/C5a paradoxically promote regeneration while exacerbating inflammation, cardiac C4d/C3d deposits correlate with rejection, and lectin pathway activation (notably via mannose-binding lectin, MBL) underlies primary graft dysfunction (PGD) in lung transplantation. Advances in therapeutic research highlight the values of complement inhibitors, including anti-C5 agents (e.g., eculizumab) that mitigate delayed graft function (DGF) in kidney transplantation, C1 esterase inhibitors that attenuate IRI and antibody-mediated rejection (AMR), C5a receptor antagonists (e.g., PMX53) that extend graft survival in preclinical models, and soluble complement receptor 1 (sCR1) that alleviates multi-organ IRI. Future research should focus on optimizing organ-specific targeting strategies, validating the long-term efficacy and safety of these agents via clinical trials, and exploring synergistic immunomodulatory approaches to further improve transplantation outcomes.