Combination effect of antithrombin and recombinant human soluble thrombomodulin in a lipopolysaccharide induced rat sepsis model
Combination effect of antithrombin and recombinant human soluble thrombomodulin in a lipopolysaccharide induced rat sepsis model
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DOI：
10.1186/cc8210
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发表时间：
2009-01-01
期刊：
影响因子：
15.1
通讯作者：
Ohno, Yoichi
中科院分区：
文献类型：
--
作者：
Iba, Toshiaki;Nakarai, Etsuro;Ohno, Yoichi
前言：重组人可溶性血栓调节蛋白(RhsTM)是新近开发的治疗DIC的药物。方法第一组大鼠分别给予6 2.5、12 5、2 5 0、5 0 0IU/kg(n=6)的AT或0.125、0.2 5、0.5、1.0 mg/kg(n=6)的重组人血凝素(Rh STM)，然后注射脂多糖。8h后检测纤维蛋白原水平。模型组给予rhsTM 0.25 mg/kg，AT组给予AT 125IU/kg，AT/TM组同时给予AT和rhsTM，对照组给予生理盐水，每组7只。检测血小板计数、纤维蛋白原、丙氨酸氨基转移酶(ALT)、乳酸脱氢酶(LDH)和高迁移率族蛋白1(HMGB1)。此外，还观察了肝脏组织学变化。结果AT和rhsTM均与纤维蛋白原水平呈线性剂量反应关系，其中125IU/kg的AT和0.25 mg/kg的rhsTM的作用相同。联合应用AT和rhsTM显著减少了血小板计数和纤维蛋白原水平的下降(P<；0.05，0.01)。各治疗组ALT、LDH升高均明显受到抑制。HMGB1水平和组织学改变倾向于表明损伤减轻。仅AT/TM组存活率显著高于对照组(P<；0.01)。结论联合应用AT和rhsTM治疗严重脓毒症可能是有效的。
Introduction Recombinant human soluble thrombomodulin (rhsTM) is newly developed for the treatment of DIC. The purpose of this study was to evaluate the efficacy of the concomitant administration of rhsTM and antithrombin (AT).Methods In the first series, rats were treated with either 62.5, 125, 250 or 500 IU/kg (n = 6, each) of AT or 0.125, 0.25, 0.5 or 1.0 mg/kg (n = 6, each) of rhsTM followed by lipopolysaccharide (LPS) injection. 8 h later, the fibrinogen level was examined. In the second series, TM group was pretreated with 0.25 mg/kg of rhsTM, AT group was pretreated with 125 IU/kg of AT, AT/TM group was pretreated with both AT and rhsTM, and control group was pretreated with saline (n = 7, each). The platelet count, fibrinogen, ALT, LDH and high-mobility group box 1 (HMGB1) levels were measured. In addition, histologic changes in liver were examined. In the third series, survival was calculated up to 24 h.Results Both AT and rhsTM produced a linear dose-response with regard to the fibrinogen level, with 125 IU/kg of AT and 0.25 mg/kg of rhsTM producing equivalent effects. The combined administration of AT and rhsTM significantly reduced the decrease in the platelet count and the fibrinogen level (P < 0.05, 0.01, respectively). The elevations in ALT and LDH were significantly suppressed in all treatment groups. The HMGB1 level and the histologic changes tended to indicate damage reduction. Survival was significantly better only in AT/TM group (P < 0.01).Conclusions The coadministration of AT and rhsTM might be effective for the treatment of severe sepsis.