title: Dissecting the complement pathway in hepatic injury and regeneration with a novel protective strategy.
abstract: Liver resection is commonly performed under ischemic conditions, resulting in two types of insult to the remnant liver: ischemia reperfusion injury (IRI) and loss of liver mass. Complement inhibition is recognized as a potential therapeutic modality for IRI, but early complement activation products are also essential for liver regeneration. We describe a novel site-targeted murine complement inhibitor, CR2-CD59, which specifically inhibits the terminal membrane attack complex (MAC), and we use this protein to investigate the complement-dependent balance between liver injury and regeneration in a clinical setting of pharmacological inhibition. CR2-CD59 did not impact in vivo generation of C3 and C5 activation products but was as effective as the C3 activation inhibitor CR2-Crry at ameliorating hepatic IRI, indicating that the MAC is the principle mediator of hepatic IRI. Furthermore, unlike C3 or C5 inhibition, CR2-CD59 was not only protective but significantly enhanced hepatocyte proliferation after partial hepatectomy, including when combined with ischemia and reperfusion. Remarkably, CR2-CD59 also enhanced regeneration after 90% hepatectomy and improved long-term survival from 0 to 70%. CR2-CD59 functioned by increasing hepatic TNF and IL-6 levels with associated STAT3 and Akt activation, and by preventing mitochondrial depolarization and allowing recovery of ATP stores.
authors.affiliation: Department of Microbiology and Immunology, Darby Children's Research Institute, and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Keely M
authors.initials: KM
authors.lastname: Marshall
authors.affiliation: Department of Microbiology and Immunology, Darby Children's Research Institute, and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425 Department of Hepatobiliary Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, People's Republic of China tomlinss@musc.edu.
authors.forename: Songqing
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Microbiology and Immunology, Darby Children's Research Institute, and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Department of Microbiology and Immunology, Darby Children's Research Institute, and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.affiliation: Department of Microbiology and Immunology, Darby Children's Research Institute, and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425 Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401 tomlinss@musc.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018957:CD59 Antigens / Q000008:administration & dosage / Q000378:metabolism; D003167:Complement Activation; D015938:Complement Membrane Attack Complex / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006498:Hepatectomy / Q000009:adverse effects; D007700:Kinetics; D008099:Liver / Q000276:immunology / Q000293:injuries* / Q000503:physiopathology; D017114:Liver Failure, Acute / Q000209:etiology / Q000276:immunology / Q000628:therapy; D008115:Liver Regeneration / Q000276:immunology* / Q000502:physiology*; D016031:Liver Transplantation / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism; D017464:Receptors, Complement 3d / Q000008:administration & dosage / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction; D014018:Tissue Distribution
chemical_list: D018957:CD59 Antigens; C527099:CR2-Crry fusion protein, mouse; D015938:Complement Membrane Attack Complex; D016207:Cytokines; D017464:Receptors, Complement 3d; D011993:Recombinant Fusion Proteins; D000255:Adenosine Triphosphate
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