Nuclear Factor κB Decoy Oligodeoxynucleotides Prevent... : Hepatology (original) (raw)

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Nuclear Factor κB Decoy Oligodeoxynucleotides Prevent Endotoxin–Induced Fatal Liver Failure in A Murine Model

Ogushi, Ichiro1; Iimuro, Yuji1; Seki, Ekihiro1; Son, Gakuhei1; Hirano, Tadamichi1; Hada, Toshikazu2; Tsutsui, Hiroko3; Nakanishi, Kenji3; Morishita, Ryuichi4; Kaneda, Yasufumi4; Fujimoto, Jiro M.D.*,1

1_First Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan_

2_Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan_

3_Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya, Japan_

4_Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan_

* First Department of Surgery, Hyogo College of Medicine, 1–1 Mukogawa–cho, Nishinomiya, Hyogo 663–8501, Japan. fax: (81) 798–45–6581; E-mail: [email protected].

Received: 19 August 2002; Accepted: 30 April 2003

Abstract

Endotoxin syndrome is a systemic inflammatory response mediated by inflammatory cytokines. Nuclear factor κB (NF–κB) is the dominant regulator of the production of these cytokines by inflammatory cells. The aim of this study was to assess the efficacy of in vivo transfer of synthetic double–stranded oligodeoxynucleotides (ODN) with high affinity against NF–κB (NF–κB/decoy/ODN) as a therapeutic strategy for treating endotoxin–induced fatal liver injury. Liver injury was induced by administration of lipopolysaccharide (LPS) to _Propionibacterium acnes_–primed BALB/C mice. NF–κB/decoy/ODN was transferred into the portal vein using a fusigenic liposome with hemagglutinating virus of Japan. NF–κB/decoy/ODN was preferentially transferred to Kupffer cells, and activation of NF–κB after the LPS challenge was suppressed, leading to decreased inflammatory cytokine production. As a result, the massive necrosis and hepatocyte apoptosis observed in the control mice was dramatically attenuated and the survival rate improved. In conclusion, NF–κB/decoy/ODN transfer in vivo effectively suppressed endotoxin–induced fatal liver injury in mice.