Neutralizing the pathological effects of extracellular histones with small polyanions.

Autor: Meara CHO; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia., Coupland LA; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia., Kordbacheh F; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia., Quah BJC; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia., Chang CW; Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia., Simon Davis DA; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia., Bezos A; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia., Browne AM; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia., Freeman C; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia., Hammill DJ; ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia., Chopra P; Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia., Pipa G; Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia., Madge PD; Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia., Gallant E; Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, 2601, Australia., Segovis C; Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, 2601, Australia., Dulhunty AF; Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, 2601, Australia., Arnolda LF; Illawarra Health and Medical Research Institute, Wollongong, NSW, 2500, Australia., Mitchell I; Intensive Care Unit, The Canberra Hospital, Garran, Canberra, ACT, 2605, Australia., Khachigian LM; Vascular Biology and Translational Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia., Stephens RW; Department of Applied Mathematics, Research School of Physics and Engineering, The Australian National University, Canberra, ACT, 2601, Australia., von Itzstein M; Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia., Parish CR; 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.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Dec 16; Vol. 11 (1), pp. 6408. Date of Electronic Publication: 2020 Dec 16.
DOI: 10.1038/s41467-020-20231-y
Abstrakt: 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.
Databáze: MEDLINE