Blog
About

  • Record: found
  • Abstract: found
  • Article: found
Is Open Access

Neutralization of CD95 ligand protects the liver against ischemia-reperfusion injury and prevents acute liver failure

Read this article at

Bookmark
      There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

      Abstract

      Ischemia-reperfusion injury is a common pathological process in liver surgery and transplantation, and has considerable impact on the patient outcome and survival. Death receptors are important mediators of ischemia-reperfusion injury, notably the signaling pathways of the death receptor CD95 (Apo-1/Fas) and its corresponding ligand CD95L. This study investigates, for the first time, whether the inhibition of CD95L protects the liver against ischemia-reperfusion injury. Warm ischemia was induced in the median and left liver lobes of C57BL/6 mice for 45 min. CD95Fc, a specific inhibitor of CD95L, was applied prior to ischemia. Hepatic injury was assessed via consecutive measurements of liver serum enzymes, histopathological assessment of apoptosis and necrosis and caspase assays at 3, 6, 12, 18 and 24 h after reperfusion. Serum levels of liver enzymes, as well as characteristic histopathological changes and caspase assays indicated pronounced features of apoptotic and necrotic liver damage 12 and 24 h after ischemia-reperfusion injury. Animals treated with the CD95L-blocker CD95Fc, exhibited a significant reduction in the level of serum liver enzymes and showed both decreased histopathological signs of parenchymal damage and decreased caspase activation. This study demonstrates that inhibition of CD95L with the CD95L-blocker CD95Fc, is effective in protecting mice from liver failure due to ischemia-reperfusion injury of the liver. CD95Fc could therefore emerge as a new pharmacological therapy for liver resection, transplantation surgery and acute liver failure.

      Related collections

      Most cited references 62

      • Record: found
      • Abstract: found
      • Article: not found

      The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion

      High-mobility group box 1 (HMGB1) is a nuclear factor that is released extracellularly as a late mediator of lethality in sepsis as well as after necrotic, but not apoptotic, death. Here we demonstrate that in contrast to the delayed role of HMGB1 in the systemic inflammation of sepsis, HMGB1 acts as an early mediator of inflammation and organ damage in hepatic ischemia reperfusion (I/R) injury. HMGB1 levels were increased during liver I/R as early as 1 h after reperfusion and then increased in a time-dependent manner up to 24 h. Inhibition of HMGB1 activity with neutralizing antibody significantly decreased liver damage after I/R, whereas administration of recombinant HMGB1 worsened I/R injury. Treatment with neutralizing antibody was associated with less phosphorylation of c-Jun NH2-terminal kinase and higher nuclear factor–κB DNA binding in the liver after I/R. Toll-like receptor 4 (TLR4)-defective (C3H/Hej) mice exhibited less damage in the hepatic I/R model than did wild-type (C3H/HeOuj) mice. Anti-HMGB1 antibody failed to provide protection in C3H/Hej mice, but successfully reduced damage in C3H/Ouj mice. Together, these results demonstrate that HMGB1 is an early mediator of injury and inflammation in liver I/R and implicates TLR4 as one of the receptors that is involved in the process.
        Bookmark
        • Record: found
        • Abstract: not found
        • Article: not found

        Necroptosis.

          Bookmark
          • Record: found
          • Abstract: found
          • Article: not found

          Lethal effect of the anti-Fas antibody in mice.

          During mammalian development, many cells are programmed to die most mediated by apoptosis. The Fas antigen coded by the structural gene for mouse lymphoproliferation mutation (lpr), is a cell surface protein belonging to the tumour necrosis factor/nerve growth factor receptor family, and mediates apoptosis. The Fas antigen messenger RNA is expressed in the thymus, liver, heart, lung and ovary. We prepared a monoclonal antibody against mouse Fas antigen, which immunoprecipitated the antigen (M(r) 45K) and had cytolytic activity against cell lines expressing mouse Fas antigen. We report here that staining of mouse thymocytes with the antibody indicated that thymocytes from the wild-type and lprcg mice expressed the Fas antigen, whereas little expression of the Fas antigen was found in lpr mice. Intraperitoneal administration of the anti-Fas antibody into mice rapidly killed the wild-type mice but neither lpr nor lprcg mice. Biochemical, histological and electron microscope analyses indicated severe damage of the liver by apoptosis. These findings suggest that the Fas antigen is important in programmed cell death in the liver, and may be involved in fulminant hepatitis in some cases.
            Bookmark

            Author and article information

            Affiliations
            [1 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of General, Visceral, and Transplant Surgery, , Heidelberg University Hospital, ; Heidelberg, Germany
            [2 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of Gastroenterology, Intoxications, and Infectious Diseases, , Heidelberg University Hospital, ; Heidelberg, Germany
            [3 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Medical Oncology, National Center for Tumor Diseases, , University of Heidelberg, ; Heidelberg, Germany
            [4 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of Pathology, , Heidelberg University Hospital, ; Heidelberg, Germany
            [5 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Division of Immunogenetics, , German Cancer Research Center, ; Heidelberg, Germany
            [6 ]ISNI 0000 0000 8988 2476, GRID grid.11598.34, Department of Surgery, Division of Transplant Surgery, , Medical University of Graz, ; Graz, Austria
            [7 ]ISNI 0000 0000 9194 7179, GRID grid.411941.8, Department of Internal Medicine I, Gastroenterology, Endocrinology, Rheumatology, and Infectious Diseases, , Regensburg University Hospital, ; Regensburg, Germany
            Contributors
            +43 316 385 14094 , Peter.Schemmer@medunigraz.at
            Journal
            Cell Death Dis
            Cell Death Dis
            Cell Death & Disease
            Nature Publishing Group UK (London )
            2041-4889
            26 January 2018
            26 January 2018
            February 2018
            : 9
            : 2
            29374146
            5833836
            150
            10.1038/s41419-017-0150-0
            © The Author(s) 2018

            Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

            Categories
            Article
            Custom metadata
            © The Author(s) 2018

            Cell biology

            Comments

            Comment on this article