Soluble Thrombomodulin Ameliorates Ischemia-Reperfusion Injury of Liver Grafts by Modulating the Proinflammatory Role of High-Mobility Group Box 1

Access this Article

Author(s)

    • Kashiwadate Toshiaki
    • Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital
    • Miyagi Shigehito
    • Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital
    • Hara Yasuyuki
    • Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital
    • Akamatsu Yorihiro
    • Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital
    • Sekiguchi Satoshi
    • Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital
    • Kawagishi Naoki
    • Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital
    • Ohuchi Noriaki
    • Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital

Abstract

<p>Transplantation using grafts obtained after cardiac death (CD) is considered a promising solution for graft shortages. However, no standard criteria for organ preservation have been established for CD donors. High-mobility group box 1 (HMGB1) is a DNA-binding protein that is released from dying hepatocytes as an early mediator of inflammation and organ tissue damage. HMGB1 stimulates immunocytes to produce inflammatory cytokines, thereby amplifying the inflammatory response. Thrombomodulin is an integral membrane protein that functions as an endothelial anticoagulant cofactor, and it binds HMGB1 through the extracellular domain. We investigated the effects of ART-123, recombinant human soluble thrombomodulin, on warm ischemia-reperfusion injury in liver grafts. Male Wistar rats were divided into four <i>ex vivo</i> groups: heart-beating (HB) group, in which livers were isolated from HB donors; CD group, in which livers were isolated from CD donors exposed to apnea-induced conditions and warm ischemic conditions for 30 min after cardiac arrest; and two CD groups pretreated with ART-123 (1 or 5 mg/kg). Each isolated liver was reperfused for 1 h after cold preservation for 6 h. The perfusate levels of HMGB1, LDH, TNF-α, and IL-6 were significantly lower in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. Bile production was significantly higher in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. The sinusoidal spaces were significantly narrower in the CD group than in the other groups. We propose that ART-123 maintains sinusoidal microcirculation by reducing endothelial cell damage during warm ischemia-reperfusion injury.</p>

Journal

  • The Tohoku Journal of Experimental Medicine

    The Tohoku Journal of Experimental Medicine 239(4), 315-323, 2016

    Tohoku University Medical Press

Codes

  • NII Article ID (NAID)
    130005169127
  • Text Lang
    ENG
  • ISSN
    0040-8727
  • Data Source
    J-STAGE 
Page Top