Is Histone a Solitary Vile Sepsis-Inducing Agent or Just "a Member of the Gang"?

Ginsburg, Isaac; Koren, Erez; Trahtemberg, Uriel; Heerden, Peter Vernon van

doi:10.4172/2332-0877.1000329

Cited by 3 publications

(3 citation statements)

References 22 publications

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“…On the other hand, circulating eHistones can associate with other components from the cell, such as double stranded (ds)DNA or high motility group box 1 (HMGB1), to form damage-associated molecular pattern molecules (DAMPs) that initiate and perpetuate systematic cytotoxic injuries through non-infectious inflammatory reactions. [17][18][19][20] In addition, the release of eHistones contributes to the formation of neutrophil extracellular traps (NETs), which results from an expulsion of various cytosolic or chromatin-related components that possess the systematic pro-inflammatory effect of NETs. 21 In healthy persons, serum levels of eHistones range from 0.79-2.30 mg/L, but in persons with sepsis, inflammation, severe trauma, and other pathological processes, eHistone levels can reach up to 230 mg/L.…”

Section: Role Of Ehistones In the Development Of Sepsis Molecular Cha...mentioning

confidence: 99%

The Role of Histones and Heparin in Sepsis: A Review

Zhang

2021

J Intensive Care Med

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Septic shock with multiple organ failure is a devastating situation in clinical settings. Through the past decades, much progress has been made in the management of sepsis and its underlying pathogenesis, but a highly effective therapeutic has not been developed. Recently, macromolecules such as histones have been targeted in the treatment of sepsis. Histones primarily function as chromosomal organizers to pack DNA and regulate its transcription through epigenetic mechanisms. However, a growing body of research has shown that histone family members can also exert cellular toxicity once they relocate from the nucleus into the extracellular space. Heparin, a commonly used anti-coagulant, has been shown to possess life-saving capabilities for septic patients, but the potential interplay between heparin and extracellular histones has not been investigated. In this review, we summarize the pathogenic roles of extracellular histones and the therapeutic roles of heparin in the development and management of sepsis and septic shock.

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Section: Role Of Ehistones In the Development Of Sepsis Molecular Cha...mentioning

confidence: 99%

The Role of Histones and Heparin in Sepsis: A Review

Zhang

2021

J Intensive Care Med

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“…Since 2009, scores of publications have also reported the presence of high levels of circulating histones in many human disorders totally unrelated to sepsis. The results by Xu et al and by Chapout et al [10,11] have also been recently challenged by several publications which had doubted whether histone is the unique "evil culprit" or just an additional marker of cell damage [37,38]. We have proposed that since activated PMNs adhering to EC may also simultaneously release into the surrounding media a plethora of pro inflammatory agonists including oxidants, histone, LL37, highly cationic elastase, cathepsins and proteinase, the treatment by the highly anionic heparin, may have actually neutralized not only cationic histone activity but mainly the synergies among the various agents.…”

Section: The Possible Role Of Cationic Histone In Sepsis Pathogenicitymentioning

confidence: 99%

The Pathogenesis of Sepsis: “If We Cannot beat them Alone Join Them?”

Korem¹,

Koren²,

Ginsburg³

2018

Microbiol Infect Dis

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Sepsis and septic shock are probably the least understood human disorders which worldwide take the lives of millions of patients. Sepsis may be defined as a multifactorial synergistic phenomenon where no unique damageassociated molecular patterns-alarming is identified which if successfully neutralized, might mitigate and protects against death in sepsis. Microorganisms which invade the blood stream may activate neutrophils to adhere to endothelial cells and to form oxidant-dependent nets rich in highly toxic nuclear histones claimed to be the main cause of death in sepsis due to the dysregulation of endothelial functions. However, the histone saga was recently critically debated since high levels circulating histones are also found in many clinical disorders unrelated to sepsis, therefore, histones may not be considered as a unique damage-associated molecular patterns-alarming but as additional markers of severe cell damage. We hereby argue that the main cause of tissue damage in sepsis may be an end result of a synergism between the numerous neutrophils pro inflammatory agents and the multiplicity of similar pro inflammatory agents generated by hemolytic steptoccocci and by additional pathogenic microorganism which recruit large numbers PMNs to the inflammatory sites. It is recommended that in sepsis caused by hemolytic streptococci and by additional toxigenic bacteria, a use of cocktails of antagonists might be more beneficial therapeutic strategies and this in view of the total failure to treat sepsis only by administrations of single antagonists. Also, targeting PMNs by immunological strategies should be sought for, to mitigate synergies between leukocytes and microbial cells.

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“…Since this study, several other papers have been published showing high levels of circulating histones in many clinical disorders unrelated to sepsis [3][4][5][6][7] . This has led to the suggestion that histones are not unique inflammation inducing alarmins (also known as damage associated molecular patterns (DAMPs)) but are actually markers of cell damage 8,9 . Notably, in the context of sepsis, highly toxic cationic histones may function not alone but in synergy with oxidants and a range of pro inflammatory agonists that are also released from activated neutrophils [10][11][12][13] .…”

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confidence: 99%