Sepsis: the dark side of histones

Chaput, Catherine; Zychlinsky, Arturo

doi:10.1038/nm1109-1245

Cited by 81 publications

(81 citation statements)

References 9 publications

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“…67,72 In this process, cytokine-induced NETosis and histone release can occur everywhere in the microvasculature, which is indicated by increased levels of histones in the circulation of septic patients. 73,74 Circulating histones cause cytotoxic impact to endothelial cells and activates platelets, which imply disseminated intravascular coagulation, tissue hypoperfusion, and organ dysfunction (e.g., of the lung, intestine, heart, kidneys). 65,73,74 These mechanisms of remote disease exacerbation apply to any source of sepsis or trauma.…”

Section: Sepsis Urosepsismentioning

confidence: 99%

“…73,74 Circulating histones cause cytotoxic impact to endothelial cells and activates platelets, which imply disseminated intravascular coagulation, tissue hypoperfusion, and organ dysfunction (e.g., of the lung, intestine, heart, kidneys). 65,73,74 These mechanisms of remote disease exacerbation apply to any source of sepsis or trauma. 75,76 Massive local DAMP or histone release can cause remote microvascular injuries and clotting (e.g., in the lung), which serves as a pathophysiologic explanation to acute respiratory distress syndrome in such settings.…”

Section: Sepsis Urosepsismentioning

confidence: 99%

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Necroinflammation in Kidney Disease

Mulay

Linkermann

Anders

2016

Journal of the American Society of Nephrology

200

185

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The bidirectional causality between kidney injury and inflammation remains an area of unexpected discoveries. The last decade unraveled the molecular mechanisms of sterile inflammation, which established danger signaling via pattern recognition receptors as a new concept of kidney injury-related inflammation. In contrast, renal cell necrosis remained considered a passive process executed either by the complement-related membrane attack complex, exotoxins, or cytotoxic T cells. Accumulating data now suggest that renal cell necrosis is a genetically determined and regulated process involving specific outside-in signaling pathways. These findings support a unifying theory in which kidney injury and inflammation are reciprocally enhanced in an autoamplification loop, referred to here as necroinflammation. This integrated concept is of potential clinical importance because it offers numerous innovative molecular targets for limiting kidney injury by blocking cell death, inflammation, or both. Here, the contribution of necroinflammation to AKI is discussed in thrombotic microangiopathies, necrotizing and crescentic GN, acute tubular necrosis, and infective pyelonephritis or sepsis. Potential new avenues are further discussed for abrogating necroinflammation-related kidney injury, and questions and strategies are listed for further exploration in this evolving field.

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Section: Sepsis Urosepsismentioning

confidence: 99%

Section: Sepsis Urosepsismentioning

confidence: 99%

Necroinflammation in Kidney Disease

Mulay

Linkermann

Anders

2016

Journal of the American Society of Nephrology

200

185

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“…1,2 Recent studies have also examined the perturbing side of histones. 3 Thus, Xu et al 4 reported that extracellular histones, which are released from dying cells, contribute to the dysfunction of endothelial cells, organ failure, and death during sepsis. In addition, endogenous histones have been reported to enhance sterile inflammation by increasing cytokine production through Toll-like receptors (TLRs).…”

mentioning

confidence: 99%

Toxic effects of extracellular histones and their neutralization by vitreous in retinal detachment

Kawano

Ito

Yamada³

et al. 2014

Laboratory Investigation

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Histones are DNA-binding proteins and are involved in chromatin remodeling and regulation of gene expression. Histones can be released after tissue injuries, and the extracellular histones cause cellular damage and organ dysfunction. Regardless of their clinical significance, the role and relevance of histones in ocular diseases are unknown. We studied the role of histones in eyes with retinal detachment (RD). Vitreous samples were collected during vitrectomy, and the concentration of histone H3 was measured by enzyme-linked immunosorbent assay. The location of the histones and related molecules was examined in a rat RD model. The release of histones and their effects on rat retinal progenitor cells R28 and ARPE-19 were evaluated in vitro. In addition, the protective role of the vitreous body against histones was tested. The intravitreal concentration of histones was higher in eyes with RD (mean, 30.9±9.8 ng/ml) than in control eyes (below the limit of detection, Po0.05). In the rat RD model, histone H3 was observed on the outer side of the detached retina and was associated with photoreceptor death. Histone H3 was released from cultured R28 by oxidative stress. Histones at a concentration 10 mg/ml induced the production of interleukin-8 in ARPE-19 cells (2.5-fold increase, Po0.05) that was mediated through the ERK1/2-and p38 MAPK-dependent pathways and Toll-like receptor 4. Histones were toxic to cells at concentrations of Z20 mg/ml. Vitreous body or hyaluronan decreased toxicity of histones by inhibiting diffusion of histones. These results indicate that histones are released from retinas with RD and may modulate the subretinal microenvironment by functioning as damage-associated molecular pattern molecules, thereby inducing proinflammatory cytokines or cell toxicity. In addition, the important role of the vitreous body and hyaluronan in protecting the retina from these toxic effects is suggested.

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“…На відміну від протабзимів сироватки крові хво-рих на СЧВ, афінно очищені IgGантитіла си-роватки крові імунізованих мишей мали високу протеолітичну активність щодо корових гістонів тимуса теляти. Ці дані заслуговують особливої уваги, оскільки було показано, що позаклітинні гістони є важливим патогенним чинником під час розвитку запальних процесів і сепсису в лю-дини [30,31]. Для дослідження протеолітичної активності АТ щодо гістонів проводили додатко-во гельфільтрацію препаратів IgG.…”

Section: результати та обговоренняunclassified