High-mobility group box 1 protein promotes development of microvascular thrombosis in rats
High-mobility group box 1 protein promotes development of microvascular thrombosis in rats
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DOI：
10.1111/j.1538-7836.2006.02255.x
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发表时间：
2007-01-01
影响因子：
10.4
通讯作者：
Maruyama, I.
中科院分区：
文献类型：
--
作者：
Ito, T.;Kawahara, K.;Maruyama, I.
背景：败血症是一种威胁生命的疾病，由感染引起的全身炎症和凝血反应引起。高迁移率族蛋白1(HMGB1)是一种含量丰富的核内蛋白，近年来被认为是脓毒症的重要致死介质。然而，HMGB1在脓毒症中发挥致死作用的确切机制尚未得到证实。我们最近报道血浆HMGB1水平与弥散性血管内凝血(DIC)评分相关，提示HMGB1可能在DIC的发病机制中起重要作用。目的：探讨HMGB1致死作用的机制，更具体地说，探讨HMGB1对凝血系统的影响。方法：用凝血酶加或不加HMGB1处理大鼠，进行生存分析、病理分析和血常规检查。体外观察HMGB1对凝血级联反应、抗凝途径及促凝血或抗凝血分子表面表达的影响。结果：与单用凝血酶相比，联合应用凝血酶和HMGB1可导致肾小球纤维蛋白沉积过多，延长血浆凝血时间，增加死亡率。在体外，HMGB1不影响凝血时间，但抑制凝血酶-血栓调节蛋白复合体介导的抗凝血蛋白C途径，并刺激单核细胞表达组织因子。结论：这些结果证实了HMGB1在体内和体外的促凝作用。脓毒症时，HMGB1在体循环中大量积聚，可促进DIC的发生发展。
Background: Sepsis is a life-threatening disorder resulting from systemic inflammatory and coagulatory responses to infection. High-mobility group box 1 protein (HMGB1), an abundant intranuclear protein, was recently identified as a potent lethal mediator of sepsis. However, the precise mechanisms by which HMGB1 exerts its lethal effects in sepsis have yet to be confirmed. We recently reported that plasma HMGB1 levels correlated with disseminated intravascular coagulation (DIC) score, indicating that HMGB1 might play an important role in the pathogenesis of DIC. Objectives: To investigate the mechanisms responsible for the lethal effects of HMGB1, and more specifically, to explore the effects of HMGB1 on the coagulation system. Methods: Rats were exposed to thrombin with or without HMGB1, and a survival analysis, pathologic analyses and blood tests were conducted. The effects of HMGB1 on the coagulation cascade, anticoagulant pathways and surface expression of procoagulant or anticoagulant molecules were examined in vitro. Results: Compared to thrombin alone, combined administration of thrombin and HMGB1 resulted in excessive fibrin deposition in glomeruli, prolonged plasma clotting times, and increased mortality. In vitro, HMGB1 did not affect clotting times, but inhibited the anticoagulant protein C pathway mediated by the thrombin-thrombomodulin complex, and stimulated tissue factor expression on monocytes. Conclusions: These findings demonstrate the procoagulant role of HMGB1 in vivo and in vitro. During sepsis, massive accumulation of HMGB1 in the systemic circulation would promote the development of DIC.