ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia.
Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia.
Nat Commun. 2020 Dec 16;11(1):6408. doi: 10.1038/s41467-020-20231-y.
Extracellular histones in neutrophil extracellular traps (NETs) or in chromatin from injured tissues are highly pathological, particularly when liberated by DNases. We report the development of small polyanions (SPAs) (~0.9-1.4 kDa) that interact electrostatically with histones, neutralizing their pathological effects. In vitro, SPAs inhibited the cytotoxic, platelet-activating and erythrocyte-damaging effects of histones, mechanistic studies revealing that SPAs block disruption of lipid-bilayers by histones. In vivo, SPAs significantly inhibited sepsis, deep-vein thrombosis, and cardiac and tissue-flap models of ischemia-reperfusion injury (IRI), but appeared to differ in their capacity to neutralize NET-bound versus free histones. Analysis of sera from sepsis and cardiac IRI patients supported these differential findings. Further investigations revealed this effect was likely due to the ability of certain SPAs to displace histones from NETs, thus destabilising the structure. Finally, based on our work, a non-toxic SPA that inhibits both NET-bound and free histone mediated pathologies was identified for clinical development.
中性粒细胞胞外诱捕网（NETs）或受损组织中的染色质中的细胞外组蛋白具有高度病理性，特别是当它们被 DNase 释放时。我们报告了小聚阴离子（SPAs）的发展，其与组蛋白静电相互作用，中和其病理作用。在体外，SPAs 抑制了组蛋白的细胞毒性、血小板激活和红细胞损伤作用，机制研究表明 SPAs 阻止了组蛋白对脂质双层的破坏。在体内，SPAs 显著抑制了败血症、深静脉血栓形成以及心脏和组织瓣缺血再灌注损伤（IRI）模型，但似乎在中和 NET 结合的组蛋白与游离组蛋白的能力上存在差异。对败血症和心脏 IRI 患者的血清分析支持了这些差异发现。进一步的研究表明，这种效应可能是由于某些 SPA 能够将组蛋白从 NETs 中置换出来，从而破坏 NETs 的结构。最后，基于我们的工作，确定了一种非毒性 SPA，它可以抑制 NET 结合和游离组蛋白介导的病理学，用于临床开发。
