Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

Authors

  • Gabriele Sass,

    1. Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany
    Search for more papers by this author
    • G.S. and S.S. contributed equally to this work.

  • Stefan Seyfried,

    1. Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany
    Search for more papers by this author
    • G.S. and S.S. contributed equally to this work.

  • Miguel Parreira Soares,

    1. Instituto Gulbenkian de Ciência, Oeiras, Portugal
    2. Immunobiology Research Center, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Kenichiro Yamashita,

    1. Immunobiology Research Center, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Elzbieta Kaczmarek,

    1. Immunobiology Research Center, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Winfried L. Neuhuber,

    1. Department of Anatomy I, University of Erlangen-Nuremberg, Erlangen, Germany
    Search for more papers by this author
  • Gisa Tiegs

    Corresponding author
    1. Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany
    • Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Fahrstrasse 17, D-91054 Erlangen, Germany
    Search for more papers by this author
    • fax: (49) 9131-85 22 774


Abstract

Induction of the heme-degrading enzyme heme oxygenase-1 (HO-1) has been shown to be beneficial in terms of improvement of liver allograft survival and prevention of CD95-mediated apoptosis in the liver. In the present study, we investigated the effects of HO-1, and its products carbon monoxide (CO), biliverdin (BV), and iron/ferritin, in a mouse model of inflammatory liver damage inducible by lipopolysaccharide (LPS) in mice sensitized with the hepatocyte-specific transcription inhibitor D-galactosamine (GalN). Our results show that HO-1 induction by cobalt-protoporphyrin-IX (CoPP) reduced cytokine expression, protected mice from liver injury, and prolonged survival. While in contrast to ferritin overexpression, single administration of the CO donor methylene chloride (MC) or of BV also protected mice from liver damage, only coadministration of both HO products prolonged survival and reduced the expression of cytokines, e.g., tumor necrosis factor (TNF) and interferon γ (IFN-γ). In conclusion, HO-1–induced prolongation of survival, but not the protection from liver damage, seems to be dependent on down-regulation of cytokine synthesis. (HEPATOLOGY 2004;40:1128–1135.)

Ancillary