TY - JOUR
T1 - Soluble thrombomodulin ameliorates ischemia-reperfusion injury of liver grafts by modulating the proinflammatory role of high-mobility group box 1
AU - Kashiwadate, Toshiaki
AU - Miyagi, Shigehito
AU - Hara, Yasuyuki
AU - Akamatsu, Yorihiro
AU - Sekiguchi, Satoshi
AU - Kawagishi, Naoki
AU - Ohuchi, Noriaki
AU - Satomi, Susumu
N1 - Funding Information:
The authors thank Yasuko Furukawa and Chikako Sato for their excellent technical assistance. The authors also acknowledge the financial support of Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Ministry of Health, Labor, and Welfare of Japan; and the Tohoku University Graduate School of Medicine.
Publisher Copyright:
© 2016 Tohoku University Medical Press.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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 mearly 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 ex vivo 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.
AB - 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 mearly 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 ex vivo 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.
KW - ART-123
KW - Donation after cardiac death
KW - HMGB1
KW - Liver
KW - Warm ischemia-reperfusion injury
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U2 - 10.1620/tjem.239.315
DO - 10.1620/tjem.239.315
M3 - Article
C2 - 27523810
AN - SCOPUS:85006817633
VL - 239
SP - 315
EP - 323
JO - Tohoku Journal of Experimental Medicine
JF - Tohoku Journal of Experimental Medicine
SN - 0040-8727
IS - 4
ER -