title: CD47 blockade reduces ischemia/reperfusion injury and improves survival in a rat liver transplantation model.
abstract: Orthotopic liver transplantation (OLT) remains the standard treatment option for nonresponsive liver failure. Because ischemia/reperfusion injury (IRI) is an important impediment to the success of OLT, new therapeutic strategies are needed to reduce IRI. We investigated whether blocking the CD47/thrombospondin-1 inhibitory action on nitric oxide signaling with a monoclonal antibody specific to CD47 (CD47mAb400) would reduce IRI in liver grafts. Syngeneic OLT was performed with Lewis rats. Control immunoglobulin G or CD47mAb400 was administered to the donor organ at procurement or to both the organ and the recipient at the time of transplant. Serum transaminases, histological changes of the liver, and animal survival were assessed. Oxidative stress, inflammatory responses, and hepatocellular damage were also quantified. A significant survival benefit was not achieved when CD47mAb400 was administered to the donor alone. However, CD47mAb400 administration to both the donor and the recipient increased animal survival afterward. The CD47mAb400-treated group showed lower serum transaminases, bilirubin, oxidative stress, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, caspase-3 activity, and proinflammatory cytokine expression of tumor necrosis factor α, interleukin-1β, and interleukin-6. Thus, CD47 blockade with CD47mAb400 administered both to the donor and the recipient reduced liver graft IRI in a rat liver transplantation model. This may translate to decreased liver dysfunction and increased survival of liver transplant recipients.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Xiao
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors.forename: Babak
authors.initials: B
authors.lastname: Banan
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors.forename: Jianluo
authors.initials: J
authors.lastname: Jia
authors.affiliation: Vasculox, Inc, St. Louis, MO.
authors.forename: Pamela T
authors.initials: PT
authors.lastname: Manning
authors.affiliation: Vasculox, Inc, St. Louis, MO.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Hiebsch
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Muthukumar
authors.initials: M
authors.lastname: Gunasekaran
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors.forename: Gundumi A
authors.initials: GA
authors.lastname: Upadhya
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO.|Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO.
authors.forename: William A
authors.initials: WA
authors.lastname: Frazier
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors.forename: Yiing
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO.
authors.forename: William C
authors.initials: WC
authors.lastname: Chapman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D051928:CD47 Antigen / Q000276:immunology / Q000378:metabolism*; D050377:Cold Ischemia / Q000009:adverse effects*; D019610:Cytoprotection; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000097:blood; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D051928:CD47 Antigen; C584934:CD47 protein, rat; D018836:Inflammation Mediators