IN VIVO AND IN VITRO EFFECTS OF THE ANTICOAGULANT, THROMBOMODULIN, ON THE INFLAMMATORY RESPONSE IN RODENT MODELS
IN VIVO AND IN VITRO EFFECTS OF THE ANTICOAGULANT, THROMBOMODULIN, ON THE INFLAMMATORY RESPONSE IN RODENT MODELS
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DOI：
10.1097/shk.0b013e3181b0ef7b
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发表时间：
2010-03-01
期刊：
影响因子：
3.1
通讯作者：
Noguchi, Takayuki
中科院分区：
文献类型：
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作者：
Hagiwara, Satoshi;Iwasaka, Hideo;Noguchi, Takayuki
脓毒症仍然是重症监护医学中的主要健康威胁。凝血级联反应的生理功能超出血液凝固，并在炎症中发挥关键作用。我们研究了是否使用重组血栓调节蛋白（rTM），其活性与抗凝血酶，组织因子途径抑制剂，和活化蛋白C，可以抑制分泌的细胞因子和高迁移率族蛋白1（HMGB 1）蛋白，从而减少肺损伤的大鼠模型的LPS诱导的全身性炎症。用静脉内注射rTM或盐水处理的大鼠与静脉内注射LPS同时注射。此外，用LPS刺激小鼠巨噬细胞RAW 264.7细胞，同时进行或不进行rTM处理。组织学检查显示，与单独给予LPS相比，用两种药物治疗后12小时收获的肺组织中的间质充血、水肿、炎症和出血显著减少。LPS诱导的促炎细胞因子和HMGB 1蛋白的分泌被rTM治疗抑制。通过免疫组织化学检查肺中HMGB 1蛋白的存在;在也接受rTM的LPS处理的动物中，HMGB 1阳性细胞的数量显著降低。在体外研究中，rTM给药通过抑制I κ B磷酸化抑制核因子-κ B的活化。抗凝剂rTM阻断了LPS诱导的炎症反应，并在该大鼠脓毒症模型中防止了通常与内毒素血症相关的急性肺损伤。鉴于这些结果，rTM是作为各种全身性炎症性疾病的治疗剂的强有力的候选者。
Sepsis remains a major health threat in intensive care medicine. The physiological functions of the coagulation cascade extend beyond blood coagulation and play a pivotal role in inflammation. We investigated whether the use of recombinant thrombomodulin (rTM), which has activity comparable with antithrombin, tissue factor pathway inhibitor, and activated protein C, could inhibit secretion of cytokines and high-mobility group box 1 (HMGB1) protein, thus reducing lung damage in a rat model of LPS-induced systemic inflammation. Rats treated with an intravenous injection of either rTM or saline were injected concurrently with intravenous LPS. In addition, mouse macrophage RAW264.7 cells were stimulated with LPS, with or without simultaneous rTM treatment. Histological examination revealed marked reductions of interstitial congestion, edema, inflammation, and hemorrhage in lung tissue harvested 12 h after treatment with both agents compared with LPS administration alone. LPS-induced secretion of proinflammatory cytokines and HMGB1 protein was inhibited by treatment with rTM. The presence of HMGB1 protein in the lung was examined by immunohistochemistry; the number of HMGB1-positive cells was significantly lower in LPS-treated animals that also received rTM. In the in vitro studies, rTM administration inhibited the activation of nuclear factor-kappa B by inhibiting I kappa B phosphorylation. The anticoagulant rTM blocked the LPS-induced inflammatory response and protected against acute lung injury normally associated with endotoxemia in this rat sepsis model. Given these results, rTM is a strong candidate as a therapeutic agent for various systemic inflammatory diseases.