Inter-α inhibitor protein and its associated glycosaminoglycans protect against histone-induced injury
Inter-α inhibitor protein and its associated glycosaminoglycans protect against histone-induced injury
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DOI：
10.1182/blood-2014-06-582759
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发表时间：
2015-04-02
期刊：
影响因子：
20.3
通讯作者：
Lupu, Florea
中科院分区：
文献类型：
--
作者：
Chaaban, Hala;Keshari, Ravi S.;Lupu, Florea
细胞外组蛋白是组织损伤和器官功能障碍的介质，因此它们构成脓毒症、炎症和血栓形成的潜在治疗靶点。组蛋白的体外细胞毒性在血浆存在下降低。在这里，我们证明了血浆内-α抑制蛋白（IAIP）中和组蛋白的细胞毒性作用，并减少组蛋白诱导的血小板聚集。这些作用通过与IAIP相关的带负电荷的糖胺聚糖（GAG）、硫酸软骨素和高分子量透明质酸（HMW-HA）介导。细胞表面阴离子糖胺聚糖、硫酸乙酰肝素和透明质酸在体外可保护细胞免受组蛋白介导的损伤。表面等离子体共振显示IAIP和HMW-HA均直接与重组组蛋白H4结合。在体内用IAIP和HMW-HA中和组蛋白可预防组蛋白诱导的血小板减少症、出血和肺微血管血栓形成，降低中性粒细胞活化，并避免组蛋白诱导的炎性细胞因子和趋化因子的产生。IAIP和HMW-HA与组蛋白共定位于坏死组织和显示中性粒细胞胞外陷阱的区域。在脓毒症狒狒血浆中检测到的IAIP-组蛋白复合物的量增加与组蛋白和/或核小体的增加以及血浆AIP的消耗相关。我们的数据表明，IAIP，硫酸软骨素，和HMW-HA是潜在的治疗剂，以防止组蛋白诱导的细胞毒性，凝血功能障碍，全身炎症，和器官损伤的炎症条件，如败血症和创伤。
Extracellular histones are mediators of tissue injury and organ dysfunction; therefore they constitute potential therapeutic targets in sepsis, inflammation, and thrombosis. Histone cytotoxicity in vitro decreases in the presence of plasma. Here, we demonstrate that plasma inter-a inhibitor protein (IAIP) neutralizes the cytotoxic effects of histones and decreases histone-induced platelet aggregation. These effects are mediated through the negatively charged glycosaminoglycans (GAGs) chondroitin sulfate and high-molecular-weight hyaluronan (HMW-HA) associated with IAIP. Cell surface anionic glycosaminoglycans heparan sulfate and HA protect the cells against histone-mediated damage in vitro. Surface plasmon resonance showed that both IAIP and HMW-HA directly bind to recombinant histone H4. In vivo neutralization of histones with IAIP and HMW-HA prevented histone-induced thrombocytopenia, bleeding, and lung microvascular thrombosis, decreased neutrophil activation, and averted histone-induced production of inflammatory cytokines and chemokines. IAIP and HMW-HA colocalized with histones in necrotic tissues and areas that displayed neutrophil extracellular traps. Increasing amounts of IAIP-histone complexes detected in the plasma of septic baboons correlated with increase in histones and/or nucleosomes and consumption of plasmaI AIP. Our data suggest that IAIP, chondroitin sulfate, and HMW-HA are potential therapeutic agents to protect against histone-induced cytotoxicity, coagulopathy, systemic inflammation, and organ damage during inflammatory conditions such as sepsis and trauma.