2. Academic Validation
  3. Neutralizing the pathological effects of extracellular histones with small polyanions

Neutralizing the pathological effects of extracellular histones with small polyanions

  • Nat Commun. 2020 Dec 16;11(1):6408. doi: 10.1038/s41467-020-20231-y.
Connor H O' Meara 1,  Lucy A Coupland 1,  Farzaneh Kordbacheh 1,  Benjamin J C Quah 1,  Chih-Wei Chang 2,  David A Simon Davis 1,  Anna Bezos 1,  Anna M Browne 1,  Craig Freeman 1,  Dillon J Hammill 1,  Pradeep Chopra 2,  Gergely Pipa 2,  Paul D Madge 2,  Esther Gallant 3,  Courtney Segovis 3,  Angela F Dulhunty 3,  Leonard F Arnolda 4,  Imogen Mitchell 5,  Levon M Khachigian 6,  Ross W Stephens 7,  Mark von Itzstein 2,  Christopher R Parish 8
Affiliations

Affiliations

  • 1 ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia.
  • 2 Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia.
  • 3 Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, 2601, Australia.
  • 4 Illawarra Health and Medical Research Institute, Wollongong, NSW, 2500, Australia.
  • 5 Intensive Care Unit, The Canberra Hospital, Garran, Canberra, ACT, 2605, Australia.
  • 6 Vascular Biology and Translational Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
  • 7 Department of Applied Mathematics, Research School of Physics and Engineering, The Australian National University, Canberra, ACT, 2601, Australia.
  • 8 ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia. christopher.parish@anu.edu.au.
PMID: 33328478 DOI: 10.1038/s41467-020-20231-y
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.

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