Extracellular histones are major mediators of death in sepsis.
Extracellular histones are major mediators of death in sepsis.
复制标题
细胞外组蛋白是败血症死亡的主要介体。
作者：
过度炎症反应可导致多种疾病，包括败血症。我们现在报告，细胞外组蛋白释放的炎症反应的挑战，有助于内皮功能障碍，器官衰竭和死亡的败血症。它们可以被组蛋白抗体或活化蛋白C（APC）靶向。组蛋白抗体可降低脂多糖（LPS）、肿瘤坏死因子（TNF）或盲肠结扎穿孔脓毒症模型小鼠的死亡率。细胞外组蛋白在体外对内皮细胞具有细胞毒性，并且在小鼠中是致命的。在体内，组蛋白给药导致中性粒细胞边集，空泡内皮细胞，肺泡内出血和大血管和微血管血栓形成。在用E.大肠埃希菌和组蛋白水平的增加伴随着肾功能不全的发作。APC切割组蛋白并降低其细胞毒性。APC与E.狒狒体内的大肠杆菌或小鼠体内的组蛋白阻止了致命性。蛋白C激活的阻断使亚致死LPS攻击加剧至致死，这被组蛋白抗体逆转。我们的结论是，细胞外组蛋白是治疗败血症和其他炎症性疾病的潜在分子靶点。
Hyper–inflammatory responses can lead to a variety of diseases including sepsis. We now report that extracellular histones released in response to inflammatory challenge contribute to endothelial dysfunction, organ failure and death during sepsis. They can be targeted pharmacologically by antibody to histone or by activated protein C (APC). Antibody to histone reduced the mortality of mice in lipopolysaccharide (LPS), tumor necrosis factor (TNF) or cecal ligation and puncture models of sepsis. Extracellular histones are cytotoxic toward endothelium in vitro and are lethal in mice. In vivo, histone administration resulted in neutrophil margination, vacuolated endothelium, intra–alveolar hemorrhage and macro and microvascular thrombosis. Histone was detected in the circulation of baboons challenged with E. coli and the increase in histone levels accompanied the onset of renal dysfunction. APC cleaves histones and reduces their cytotoxicity. Co–infusion of APC with E. coli in baboons or histones in mice prevented lethality. Blockade of protein C activation exacerbated sublethal LPS challenge into lethality which was reversed by antibody to histone. We conclude that extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases.