Histidine-Rich Glycoprotein Prevents Septic Lethality through Regulation of Immunothrombosis and Inflammation.
Histidine-Rich Glycoprotein Prevents Septic Lethality through Regulation of Immunothrombosis and Inflammation.
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DOI：
10.1016/j.ebiom.2016.06.003
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发表时间：
2016-07
期刊：
影响因子：
11.1
通讯作者：
Nishibori M
中科院分区：
文献类型：
--
作者：
Wake H;Mori S;Liu K;Morioka Y;Teshigawara K;Sakaguchi M;Kuroda K;Gao Y;Takahashi H;Ohtsuka A;Yoshino T;Morimatsu H;Nishibori M
脓毒症是全世界死亡的主要原因。我们发现，在盲肠结扎和穿刺（CLP）的脓毒症小鼠中，血浆蛋白富组氨酸糖蛋白（HRG）显著降低，用外源性HRG补充治疗脓毒症小鼠可以提高存活率，并强烈抑制中性粒细胞与肺血管的紧密附着，随后的免疫血栓形成，DIC状态，肺部炎症，高细胞素血症和血管内皮细胞（VECs）的激活。相反，siRNA敲低HRG会加重致死性。纯化的人HRG在体外可逆诱导人中性粒细胞形态变化；微绒毛减少的球形诱导和对VECs的粘附性。HRG维持了中性粒细胞通过微血管的通道，并消除了活性氧的产生。这些结果表明，HRG的补充治疗可能为脓毒症的治疗提供了一种新的策略，通过保持循环中性粒细胞静止和防止VECs失控激活来抑制过度的全身炎症和免疫血栓形成。高致死率脓毒症小鼠血浆蛋白HRG显著降低。HRG辅助治疗可提高脓毒症小鼠的存活率。HRG治疗可抑制免疫血栓形成、NETosis和过度炎症。HRG使循环中性粒细胞在形态和功能上保持静止。脓毒症是重症监护病房中一种死亡率高、主要死亡原因的危重疾病，但目前尚无针对脓毒症的治疗药物。本研究发现，在脓毒症小鼠模型中，血浆蛋白富组氨酸糖蛋白（HRG）显著降低，用纯化的人HRG补充治疗脓毒症小鼠，显著提高小鼠的致死率，这与抑制中性粒细胞与肺血管的紧密附着、随后的血栓形成、肺部炎症和血管内皮细胞的活化有关。因此，HRG辅助治疗可能为脓毒症患者提供一种新的治疗策略。
Sepsis is a major cause of death worldwide. We show that a plasma protein histidine-rich glycoprotein (HRG) was decreased significantly in septic mice with cecal ligation and puncture (CLP) and supplementary treatment of septic mice with exogenous HRG improved survival, with strong inhibition of tight attachment of neutrophils to pulmonary vasculatures, subsequent immunothrombosis, DIC state, lung inflammation, hypercytokinemia, and activation of vascular endothelial cells (VECs). In contrast, knockdown of HRG by siRNA exacerbated lethality. Purified human HRG reversibly induced morphological changes in human neutrophils in vitro; induction of spherical shape with reduced microvilli and adhesiveness to VECs. HRG maintained the passage of neutrophils through microcapillaries and abolished production of reactive oxygen species. These results suggested that the supplementary therapy with HRG may provide a novel strategy for the treatment of sepsis through suppression of excessive systemic inflammation and immunothrombosis by keeping circulating neutrophils quiescent and preventing uncontrolled activation of VECs. A plasma protein HRG decreased markedly in septic mice with high lethality. Supplementary treatment with HRG improved the survival of septic mice. HRG treatment inhibited immunothrombosis, NETosis, and excessive inflammation. HRG kept circulating neutrophils quiescent morphologically and functionally. Although sepsis is a critical disease condition with high mortality and the main cause of death in intensive care units, there is no therapeutic drug for sepsis now. This research found that a plasma protein, histidine-rich glycoprotein (HRG), decreased dramatically in sepsis mouse model and that supplementary treatment of septic mice with purified human HRG remarkably improved the lethality of mice, associated with inhibition of tight attachment of neutrophils to pulmonary vasculatures, subsequent thrombosis, lung inflammation and activation of vascular endothelial cells. Thus, supplementary therapy with HRG may provide a novel strategy for the treatment of septic patients.