Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia
Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia
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DOI：
10.1097/ccm.0b013e3181a55184
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发表时间：
2009-07-01
影响因子：
8.8
通讯作者：
Yamaguchi, Koji
中科院分区：
文献类型：
--
作者：
Nagato, Masaru;Okamoto, Kohji;Yamaguchi, Koji
目的：新近发现的致死性晚期介质高迁移率族蛋白-1(HMGB1)除与炎性细胞因子过度激活外，还与脓毒症的发生发展密切相关。因此，本研究旨在观察重组人可溶性血栓调节蛋白(ART-123)对实验性内毒素血症大鼠炎症细胞因子产生及血浆HMGB1水平的影响。设计：前瞻性、对照、实验研究。研究背景：实验动物研究中心。对象：雄性SD大鼠(250-300g)。干预：内毒素血症大鼠静脉注射脂多糖(LPS)4 mg/kg。ART-123(11 mg/kg)于注射内毒素前30分钟或注射后4小时团注(ART-123预/治疗组)。用等量生理盐水代替脂多糖和ART-123(对照组)作为对照。测量和主要结果：大鼠随机分为ART-123预处理组、ART-123处理组和脂多糖组。注射脂多糖后，观察炎性细胞因子、凝血酶-抗凝血酶-抗凝血酶III复合体水平、血浆HMGB1浓度、肝脏免疫组织化学及肝组织病理学变化、肝功能损害及存活率。ART-123可改善内毒素诱导的炎性细胞因子水平和血浆HMGB1水平的升高，减轻肝功能损害，提高存活率。本研究证实ART-123可抑制实验性内毒素血症时炎症细胞因子的表达，降低血浆HMGB1水平。此外，即使延缓了ART-123的治疗，ART-123的应用也显著减少了肝功能障碍和死亡率。因此，ART-123的使用可能是败血症患者的一种有益的治疗方法。(Crit Care Med 2009；37：2181-2186)
Objective: In addition to the hyperactivation of the inflammatory cytokines, high-mobility group box-1 protein (HMGB1), recently identified as a lethal late-phase mediator is suspected to be closely correlated with the development of sepsis. Therefore, the therapeutic efficacy of recombinant human soluble thrombomodulin (ART-123) administration on the production of inflammatory cytokines and the plasma level of HMGB1 was investigated in experimental endotoxemia.Design: Prospective, comparative, experimental study.Setting., Laboratory animal research center at a university.Subjects: Male Sprague-Dawley rats (250-300 g).Interventions: Endotoxemia was induced in rats by a bolus intravenous injection of lipopolysaccharide (LPS) at a dosage of 4 mg/kg (LPS group). ART-123 (11 mg/kg) was administered as a bolus injection 30 minutes before or 4 hours after injection of LPS (ART-123 pretreated/treated group). As a control, an equal volume of physiologic saline was administered instead of LPS and ART-123 (control group).Measurements and Main Results, Rats were randomly divided into ART-123 pretreated group, ART-123 treated group, and LPS group, respectively. After the injection of LPS, the levels of inflammatory cytokines and thrombin-antithrombin III complex, plasma HMGB1 concentrations, liver immunohistochemical and histopathologic characteristics, liver dysfunction, and survival rate were examined. The increased levels of inflammatory cytokines and plasma HMGB1 induced by LPS in this rat model were improved by the administration of ART-123; additionally, reduced liver dysfunction and increased survival rate were observed.Conclusions. This study demonstrated that ART-123 inhibits the expression of inflammatory cytokines and decreases the plasma HMGB1 levels in experimental endotoxemia. In addition, ART-123 administration markedly reduced liver dysfunction and mortality even with delayed treatment of ART-123. The use of ART-123 may therefore be a beneficial treatment for septic patients. (Crit Care Med 2009; 37:2181-2186)