TY - JOUR
T1 - The lectin-like domain of thrombomodulin is a drug candidate for both prophylaxis and treatment of liver ischemia and reperfusion injury in mice
AU - Kawasoe, Junya
AU - Uchida, Yoichiro
AU - Miyauchi, Tomoyuki
AU - Kadono, Kentaro
AU - Hirao, Hirofumi
AU - Saga, Kenichi
AU - Watanabe, Takeshi
AU - Ueda, Shugo
AU - Terajima, Hiroaki
AU - Uemoto, Shinji
N1 - Funding Information:
We thank Masaaki Fujita, MD, PhD, at the Department of Clinical Immunology for helpful instructions, Marika Hirao, PhD, for technical assistance, and Koichi Hirano for animal care at The Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan. This study was supported by a Grant‐in‐Aid for Scientific Research (C) (15K10041) from the Ministry of Education, Culture, Science and Sports, Japan and by Kitano Research Grant from The Tazuke Kofukai Medical Research Institute, Kitano Hospital.
Publisher Copyright:
© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2021/2
Y1 - 2021/2
N2 - Ischemia and reperfusion injury (IRI) can occur in any tissue or organ. With respect to liver transplantation, the liver grafts from donors by definition experience transient ischemia and subsequent blood reflow. IRI is a problem not only in organ transplantation but also in cases of thrombosis or circulatory disorders such as mesenteric ischemia, myocardial, or cerebral infarction. We have reported that recombinant human soluble thrombomodulin (rTM), which is currently used in Japan to treat disseminated intravascular coagulation (DIC), has a protective effect and suppresses liver IRI in mice. However, rTM may not be fully safe to use in humans because of its inherent anticoagulant activity. In the present study, we used a mouse liver IRI model to explore the possibility that the isolated lectin-like domain of rTM (rTMD1), which has no anticoagulant activity, could be effective as a therapeutic modality for IRI. Our results indicated that rTMD1 could suppress ischemia and reperfusion-induced liver damage in a dose-dependent manner without concern of associated hemorrhage. Surprisingly, rTMD1 suppressed the liver damage even after IR insult had occurred. Taken together, we conclude that rTMD1 may be a candidate drug for prevention of and therapy for human liver IRI without the possible risk of hemorrhage.
AB - Ischemia and reperfusion injury (IRI) can occur in any tissue or organ. With respect to liver transplantation, the liver grafts from donors by definition experience transient ischemia and subsequent blood reflow. IRI is a problem not only in organ transplantation but also in cases of thrombosis or circulatory disorders such as mesenteric ischemia, myocardial, or cerebral infarction. We have reported that recombinant human soluble thrombomodulin (rTM), which is currently used in Japan to treat disseminated intravascular coagulation (DIC), has a protective effect and suppresses liver IRI in mice. However, rTM may not be fully safe to use in humans because of its inherent anticoagulant activity. In the present study, we used a mouse liver IRI model to explore the possibility that the isolated lectin-like domain of rTM (rTMD1), which has no anticoagulant activity, could be effective as a therapeutic modality for IRI. Our results indicated that rTMD1 could suppress ischemia and reperfusion-induced liver damage in a dose-dependent manner without concern of associated hemorrhage. Surprisingly, rTMD1 suppressed the liver damage even after IR insult had occurred. Taken together, we conclude that rTMD1 may be a candidate drug for prevention of and therapy for human liver IRI without the possible risk of hemorrhage.
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U2 - 10.1111/ajt.16269
DO - 10.1111/ajt.16269
M3 - Article
C2 - 32805077
AN - SCOPUS:85091345895
VL - 21
SP - 540
EP - 551
JO - American Journal of Transplantation
JF - American Journal of Transplantation
SN - 1600-6135
IS - 2
ER -