Circulating Histones Are Major Mediators of Cardiac Injury in Patients With Sepsis*

Alhamdi, Yasir; Abrams, Simon T.; Cheng, Zhaojun; Jing, Shengjie; Su, Dunhao; Li, Yong; Lane, Steven; Welters, Ingeborg; Wang, Guozheng; Toh, Cheng‐Hock

doi:10.1097/ccm.0000000000001162

Cited by 145 publications

(185 citation statements)

References 44 publications

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“…Furthermore, in a mouse sepsis model, a similarly sized histone H3 fragment was found in the circulation, although its origin remained unclear. 49 This truncated form of histone H3 is reminiscent of the band observed upon incubation of purified nucleosomes with active FSAP and was not observed upon incubation with FSAP-deficient serum. However, we cannot exclude that other proteases may also be involved in histone H3 proteolysis, 52 because intracellular proteases, including cathepsin L, are known to cleave H3 to a similarly sized band.…”

Section: Discussionmentioning

confidence: 99%

“…The size of the chromatin fragments, presence of antimicrobial proteins, and different histone modifications that modulate chromatin condensation, and thus histone exposure, may have influenced NET cytotoxicity. Because injection of anti-histone antibodies had beneficial effects in mouse and baboon sepsis, 11,49 and our results suggest that histones circulate as nucleosomes that are not cytotoxic in vitro, other mechanisms must be involved in nucleosome-induced inflammation.…”

Section: Discussionmentioning

confidence: 99%

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DNA and factor VII–activating protease protect against the cytotoxicity of histones

et al. 2017

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Key Points• Free histones, not nucleosomes, are cytotoxic and are degraded by FSAP in serum to protect against cytotoxicity.• Free histone H3 was not detectable in sera of septic baboons and patients with meningococcal sepsis.Circulating histones have been implicated as major mediators of inflammatory disease because of their strong cytotoxic effects. Histones form the protein core of nucleosomes;however, it is unclear whether histones and nucleosomes are equally cytotoxic. Several plasma proteins that neutralize histones are present in plasma. Importantly, factor VII-activating protease (FSAP) is activated upon contact with histones and subsequently proteolyzes histones. We aimed to determine the effect of FSAP on the cytotoxicity of both histones and nucleosomes. Indeed, FSAP protected against histone-induced cytotoxicity of cultured cells in vitro. Upon incubation of serum with histones, endogenous FSAP was activated and degraded histones, which also prevented cytotoxicity. Notably, histones as part of nucleosome complexes were not cytotoxic, whereas DNA digestion restored cytotoxicity. Histones in nucleosomes were inefficiently cleaved by FSAP, which resulted in limited cleavage of histone H3 and removal of the N-terminal tail. The specific isolation of either circulating nucleosomes or free histones from sera of Escherichia coli challenged baboons or patients with meningococcal sepsis revealed that histone H3 was present in the form of nucleosomes, whereas free histone H3 was not detected. All samples showed signs of FSAP activation. Markedly, we observed that all histone H3 in nucleosomes from the patients with sepsis, and most histone H3 from the baboons, was N-terminally truncated, giving rise to a similarly sized protein fragment as through cleavage by FSAP.Taken together, our results suggest that DNA and FSAP jointly limit histone cytotoxicity and that free histone H3 does not circulate in appreciable concentrations in sepsis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

DNA and factor VII–activating protease protect against the cytotoxicity of histones

et al. 2017

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“…Cellular injury mediated by extracellular histones has been described experimentally or in human disease of the lung,94 heart,95 liver,96 kidney31 and vascular endothelium 62. Table 2 details the effects of extracellular histones observed in specific cell types.…”

Section: Molecular Basis Of Histone‐related Cellular and Tissue Injurymentioning

confidence: 99%

Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

Szatmary

Huang

Criddle

et al. 2018

J Cellular Molecular Medi

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Histones are positively charged nuclear proteins that facilitate packaging of DNA into nucleosomes common to all eukaryotic cells. Upon cell injury or cell signalling processes, histones are released passively through cell necrosis or actively from immune cells as part of extracellular traps. Extracellular histones function as microbicidal proteins and are pro‐thrombotic, limiting spread of infection or isolating areas of injury to allow for immune cell infiltration, clearance of infection and initiation of tissue regeneration and repair. Histone toxicity, however, is not specific to microbes and contributes to tissue and end‐organ injury, which in cases of systemic inflammation may lead to organ failure and death. This review details the processes of histones release in acute inflammation, the mechanisms of histone‐related tissue toxicity and current and future strategies for therapy targeting histones in acute inflammatory diseases.

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“…We are now also waiting for the development of effective antihistone strategies to verify that this polycation is indeed the major "virulence factor" but maybe that histone does not function on its own, but in synergy with additional agonists. The following recent publications on histone and sepsis are worth reading [51][52][53][54][55][56][57][58][59][60][61].…”

Section: "Miracle Histones": Is It a Breakthrough In Sepsis Research?mentioning

confidence: 99%

Synergistic Aspects to Explain the Pathophysiology of Sepsis and Septic Shock-An Opinion

Koren¹,

Ginsburg²

2015

J Infect Dis Ther

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Circulating Histones Are Major Mediators of Cardiac Injury in Patients With Sepsis*

Abstract: Circulating histones are novel and important mediators of septic cardiomyopathy, which can potentially be utilized for prognostic and therapeutic purposes.

Cited by 145 publications

References 44 publications

DNA and factor VII–activating protease protect against the cytotoxicity of histones

DNA and factor VII–activating protease protect against the cytotoxicity of histones

Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

Synergistic Aspects to Explain the Pathophysiology of Sepsis and Septic Shock-An Opinion

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