The protective role of CD59 and pathogenic role of complement in hepatic ischemia and reperfusion injury.
Hepatic ischemia-reperfusion injury (IRI) is a major factor influencing graft outcome in liver transplantation, but its mechanism is not well defined. Although complement, including the membrane attack complex (MAC), a terminal product of complement activation, is thought to be involved in the multiple reactions subsequent to the ischemia-reperfusion (IR) process, the role of MAC in the pathogenesis of hepatic IRI requires further investigation. We used a warm ischemia-reperfusion injury model in mice and a syngeneic orthotopic liver transplantation model in rats to define the role of complement, including MAC, in hepatic IR. CD59-deficient mice had more severe liver dysfunction, evidenced by increased aspartate aminotransferase levels and increased injury of liver parenchymal and nonparenchymal cells than did CD59-sufficient mice during warm hepatic IR. Furthermore, complement depletion in CD59-deficient mice by pretreatment with cobra venom factor (CVF) or the genetic introduction of C3 deficiency partially protected against development of the severe liver dysfunction that occurred in CD59-deficient mice. Severity of liver dysfunction correlated with MAC deposition, apoptotic cells, and increased inflammatory mediators such as tumor necrosis factor α. Moreover, depletion of complement with CVF in orthotopic liver transplantation recipient rats attenuated IRI of the donor livers. Taken together, these results highlight the protective role of CD59 and pathogenic role of complement, including MAC, in the pathogenesis of hepatic IRI.
Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.
Jinyan
J
Zhang
Weiguo
W
Hu
Wei
W
Xing
Tao
T
You
Junming
J
Xu
Xuebin
X
Qin
Zhihai
Z
Peng
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001219:Aspartate Aminotransferases / Q000097:blood; D018957:CD59 Antigens / Q000502:physiology*; D002460:Cell Line; D003167:Complement Activation / Q000276:immunology*; D003176:Complement C3 / Q000172:deficiency; D051056:Complement Inactivating Agents / Q000494:pharmacology; D015938:Complement Membrane Attack Complex / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004546:Elapid Venoms / Q000494:pharmacology; D006085:Graft Survival / Q000276:immunology; D008099:Liver / Q000098:blood supply; D008107:Liver Diseases / Q000276:immunology*; D016031:Liver Transplantation / Q000276:immunology* / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D015427:Reperfusion Injury / Q000209:etiology* / Q000276:immunology; D052096:Warm Ischemia / Q000379:methods
D018957:CD59 Antigens; D003176:Complement C3; D051056:Complement Inactivating Agents; D015938:Complement Membrane Attack Complex; D016207:Cytokines; D004546:Elapid Venoms; C016310:cobra venom factor; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase