title: Human C1 inhibitor attenuates liver ischemia-reperfusion injury and promotes liver regeneration.
abstract: Liver ischemia-reperfusion injury (IRI) is a well-known cause of morbidity and mortality after liver transplantation (LT). Activation of the complement system contributes to the pathogenesis of IRI. Effective treatment strategies aimed at reducing hepatic IRI and accelerating liver regeneration could offer major benefits in LT. Herein, we investigated the effect of C1-esterase inhibitor (human) [C1-INH] on IRI and liver regeneration. Mice were subjected to 60-min partial IRI, with or without 70% partial hepatectomy, or CCl4-induced acute liver failure. Before liver injury, the animals were pretreated with intravenous C1-INH or normal saline. Liver IRI was evaluated using serum levels of alanine aminotransferase, serum interleukin-6, and histopathology. Liver samples were stained for specific markers of regeneration (5-bromo-2'-deoxyuridine [BrdU] staining and proliferating cell nuclear antigen [PCNA]). Histology, serum interleukin-6, and alanine aminotransferase release revealed that C1-INH treatment attenuated liver injury compared with controls. Improved animal survival and increased number of BrdU- and PCNA-positive cells were observed in C1-INH-treated animals which underwent IRI + partial hepatectomy or CCl4 injection compared with control group. These data indicate that complement plays a key role in IRI and liver regeneration. C1-INH represents a potential therapeutic strategy to reduce IRI and promote regeneration in LT.
authors.affiliation: Division of Organ Transplantation, Department of Surgery, Alpert Medical School of Brown University, Providence, Rhode Island. Electronic address: rfsaidi@hotmail.com.
authors.forename: Reza F
authors.initials: RF
authors.lastname: Saidi
authors.affiliation: Division of Organ Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Barur
authors.initials: B
authors.lastname: Rajeshkumar
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Shariftabrizi
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Karen
authors.initials: K
authors.lastname: Dresser
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Otto
authors.initials: O
authors.lastname: Walter
mesh_terms: D000818:Animals; D050718:Complement C1 Inhibitor Protein / Q000378:metabolism / Q000494:pharmacology*; D003176:Complement C3 / Q000235:genetics; D006498:Hepatectomy / Q000379:methods; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000502:physiology / Q000601:surgery; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000209:etiology* / Q000401:mortality; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D016031:Liver Transplantation / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D050718:Complement C1 Inhibitor Protein; D003176:Complement C3; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: Acute liver failure; Complement inhibition; Complement system; Liver ischemia-reperfusion injury; Regeneration