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  • Neutralizing the pathological effects of extracellular histones with small polyanions.

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    Chang455783-Published.pdf (3.215Mb)
    Author(s)
    Meara, Connor H O'
    Coupland, Lucy A
    Kordbacheh, Farzaneh
    Quah, Benjamin JC
    Chang, Chih-Wei
    Simon Davis, David A
    Bezos, Anna
    Browne, Anna M
    Freeman, Craig
    Hammill, Dillon J
    Chopra, Pradeep
    Pipa, Gergely
    Madge, Paul D
    von Itzstein, Mark
    et al.
    Griffith University Author(s)
    Chang, Chih-Wei
    von Itzstein, Mark
    Year published
    2020
    Metadata
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    Abstract
    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 ...
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    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.
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    Journal Title
    Nature Communications
    Volume
    11
    Issue
    1
    DOI
    https://doi.org/10.1038/s41467-020-20231-y
    Copyright Statement
    © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
    Subject
    Clinical Sciences
    Publication URI
    http://hdl.handle.net/10072/400442
    Collection
    • Journal articles

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