トロンボモジュリン  [in Japanese] Thrombomodulin  [in Japanese]

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Author(s)

Abstract

天然型のヒト可溶性トロンボモジュリン (MR・33) は,ヒト血漿を用いた in vitro 試験において,トロンビンの凝固促進作用を抑制するとともに,プロテインC (PC) 活性化を介して,トロンビンの産生を抑制した.また MR-33は,ATIII非依存的に抗凝固作用を発揮するとともに,ラット DIC モデルにおいて,抗凝固薬の副作用となる出血を助長することなく凝固亢進を改善した.さらに, MR-33 は,マウス肺障害モデルあるいは虚血再灌流によるラット臓器障害モデルにおいて,凝固異常を改善するとともに,サイトカインの産生を抑制し,臓器障害の進展を阻止することが明らかとなった.これらのことより, MR-33 は, DIC の治療薬として優れており,また,臓器障害を伴う疾患に対しても有用であることが期待される.

Thrombomodulin (TM), a membrane-bound receptor for thrombin on the endothelial cell surface, contributes to the regulation of the coagulation system. TM is known to exist in human plasma and urine as soluble forms. We purified soluble TM from human urine (MR-33) and investigated the anticoagulant effects of MR-33 in vitro and in vivo. In human plasma, MR-33 inhibited not only the procoagulant activity of thrombin, but also the thrombin generation via accelerating the thrombin-catalyzed protein C activation. In rat disseminated intravascular coagulation (DIC) models, intravenous infusion of MR-33 improved the hematological abnormalities without excessive prolongation of APTT and bleeding time. Benefit (dose required for 50% inhibition of fibrinogen decrease: ED50) to risk (minimum dose required for significant prolongation of bleeding time) ratio was 1:27 for MR-33. Furthermore, the anticoagulant activities of MR-33 was independent of AT III activity, and MR-33 was effective on heparin-resistant DIC models with low AT III level in rats. Intravenous injection of MR-33 prevented the endotoxin-induced increases in TAT, TNF-α and IL-6 level and pulmonary vascular permeability in mice. These results indicate that MR-33 may be a clinically useful antithrombotic agent with reduced risk for hemorrhage, and this drug also has antiinflammatory effects. Clinical trials of MR-33 for the treatment of DIC are now in progress in Japan.

Journal

  • Folia Pharmacologica Japonica

    Folia Pharmacologica Japonica 116(5), 283-289, 2000-11-01

    The Japanese Pharmacological Society

References:  24

Codes

  • NII Article ID (NAID)
    10008181235
  • NII NACSIS-CAT ID (NCID)
    AN00198335
  • Text Lang
    JPN
  • Article Type
    REV
  • ISSN
    00155691
  • NDL Article ID
    5539822
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z19-247
  • Data Source
    CJP  NDL  J-STAGE 
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