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      Neutralizing the pathological effects of extracellular histones with small polyanions

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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 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.

          Abstract

          Histones, proteins that bind DNA, are toxic for pathogens outside cells but can also cause multi-organ damage as seen in sepsis. Here the authors develop small negatively charged molecules that can be used as histone antidotes, and show that they improve the phenotype in mouse models with histone-related pathologies.

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          Most cited references85

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          Neutrophil extracellular traps kill bacteria.

          Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, we describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria. These neutrophil extracellular traps (NETs) degrade virulence factors and kill bacteria. NETs are abundant in vivo in experimental dysentery and spontaneous human appendicitis, two examples of acute inflammation. NETs appear to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concentration of antimicrobial agents to degrade virulence factors and kill bacteria.
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            APACHE II: a severity of disease classification system.

            This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases. When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
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              Neutrophil extracellular traps in COVID-19

              In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have the potential to propagate inflammation and microvascular thrombosis — including in the lungs of patients with acute respiratory distress syndrome. We now report that sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase-DNA (MPO-DNA), and citrullinated histone H3 (Cit-H3); the latter 2 are specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute-phase reactants, including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19. Serum levels of neutrophil extracellular traps identify COVID-19 patients with more severe respiratory disease.
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                Author and article information

                Contributors
                christopher.parish@anu.edu.au
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                16 December 2020
                16 December 2020
                2020
                : 11
                : 6408
                Affiliations
                [1 ]GRID grid.1001.0, ISNI 0000 0001 2180 7477, ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, , The Australian National University, ; Canberra, ACT 2601 Australia
                [2 ]GRID grid.1022.1, ISNI 0000 0004 0437 5432, Institute for Glycomics, , Griffith University, ; Gold Coast, QLD 4222 Australia
                [3 ]GRID grid.1001.0, ISNI 0000 0001 2180 7477, 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 ]GRID grid.413314.0, ISNI 0000 0000 9984 5644, Intensive Care Unit, , The Canberra Hospital, ; Garran, Canberra, ACT 2605 Australia
                [6 ]GRID grid.1005.4, ISNI 0000 0004 4902 0432, Vascular Biology and Translational Research, School of Medical Sciences, , University of New South Wales, ; Sydney, NSW 2052 Australia
                [7 ]GRID grid.1001.0, ISNI 0000 0001 2180 7477, Department of Applied Mathematics, Research School of Physics and Engineering, , The Australian National University, ; Canberra, ACT 2601 Australia
                Author information
                http://orcid.org/0000-0002-6944-6938
                http://orcid.org/0000-0002-8912-9534
                http://orcid.org/0000-0002-5009-0302
                http://orcid.org/0000-0002-9592-9474
                http://orcid.org/0000-0003-4609-0147
                http://orcid.org/0000-0003-3446-0323
                http://orcid.org/0000-0001-6124-0102
                http://orcid.org/0000-0001-6302-7524
                http://orcid.org/0000-0001-7740-0430
                Article
                20231
                10.1038/s41467-020-20231-y
                7744542
                33328478
                69425f7c-56dd-4d06-a3fe-e51617454ace
                © The Author(s) 2020

                Open Access 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 11 December 2019
                : 19 November 2020
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                © The Author(s) 2020

                Uncategorized
                innate immunity,drug development
                Uncategorized
                innate immunity, drug development

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