IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-20231-y.html
   My bibliography  Save this article

Neutralizing the pathological effects of extracellular histones with small polyanions

Author

Listed:
  • Connor H. O’ Meara

    (The Australian National University)

  • Lucy A. Coupland

    (The Australian National University)

  • Farzaneh Kordbacheh

    (The Australian National University)

  • Benjamin J. C. Quah

    (The Australian National University)

  • Chih-Wei Chang

    (Griffith University)

  • David A. Simon Davis

    (The Australian National University)

  • Anna Bezos

    (The Australian National University)

  • Anna M. Browne

    (The Australian National University)

  • Craig Freeman

    (The Australian National University)

  • Dillon J. Hammill

    (The Australian National University)

  • Pradeep Chopra

    (Griffith University)

  • Gergely Pipa

    (Griffith University)

  • Paul D. Madge

    (Griffith University)

  • Esther Gallant

    (Australian National University)

  • Courtney Segovis

    (Australian National University)

  • Angela F. Dulhunty

    (Australian National University)

  • Leonard F. Arnolda

    (Illawarra Health and Medical Research Institute)

  • Imogen Mitchell

    (The Canberra Hospital)

  • Levon M. Khachigian

    (University of New South Wales)

  • Ross W. Stephens

    (The Australian National University)

  • Mark Itzstein

    (Griffith University)

  • Christopher R. Parish

    (The Australian National University)

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 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.

Suggested Citation

  • Connor H. O’ Meara & Lucy A. Coupland & Farzaneh Kordbacheh & Benjamin J. C. Quah & Chih-Wei Chang & David A. Simon Davis & Anna Bezos & Anna M. Browne & Craig Freeman & Dillon J. Hammill & Pradeep Ch, 2020. "Neutralizing the pathological effects of extracellular histones with small polyanions," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20231-y
    DOI: 10.1038/s41467-020-20231-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-20231-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-20231-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20231-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.