Extracellular histones are major mediators of death in sepsis
Jun Xu,Xiaomei Zhang,Rosana Pelayo,Marc Monestier,Concetta T. Ammollo,Fabrizio Semeraro,Fletcher B. Taylor,Naomi L. Esmon,Florea Lupu,Charles T. Esmon,Charles T. Esmon +10 more
TLDR
It is concluded that extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases.Abstract:
Hyperinflammatory responses can lead to a variety of diseases, including sepsis. We now report that extracellular histones released in response to inflammatory challenge contribute to endothelial dysfunction, organ failure and death during sepsis. They can be targeted pharmacologically by antibody to histone or by activated protein C (APC). Antibody to histone reduced the mortality of mice in lipopolysaccharide (LPS), tumor necrosis factor (TNF) or cecal ligation and puncture models of sepsis. Extracellular histones are cytotoxic toward endothelium in vitro and are lethal in mice. In vivo, histone administration resulted in neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage and macro- and microvascular thrombosis. We detected histone in the circulation of baboons challenged with Escherichia coli, and the increase in histone levels was accompanied by the onset of renal dysfunction. APC cleaves histones and reduces their cytotoxicity. Co-infusion of APC with E. coli in baboons or histones in mice prevented lethality. Blockade of protein C activation exacerbated sublethal LPS challenge into lethality, which was reversed by treatment with antibody to histone. We conclude that extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases.read more
Citations
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Molecular mechanisms of necroptosis: an ordered cellular explosion.
TL;DR: Evidence now reveals that necrosis can also occur in a regulated manner, and necroptosis participates in the pathogenesis of diseases, including ischaemic injury, neurodegeneration and viral infection, thereby representing an attractive target for the avoidance of unwarranted cell death.
Journal ArticleDOI
Extracellular DNA traps promote thrombosis
Tobias A. Fuchs,Alexander Brill,Daniel Duerschmied,Daphne Schatzberg,Marc Monestier,Daniel D. Myers,Shirley K. Wrobleski,Thomas W. Wakefield,John H. Hartwig,Denisa D. Wagner +9 more
TL;DR: It is reported that NETs provide a heretofore unrecognized scaffold and stimulus for thrombus formation and may further explain the epidemiological association of infection with thrombosis.
Journal ArticleDOI
Neutrophil extracellular traps in immunity and disease
TL;DR: The identification of molecules that modulate the release of NETs has helped to refine the view of the role of neutrophils in immune protection, inflammatory and autoimmune diseases and cancer.
Journal ArticleDOI
The acute respiratory distress syndrome.
TL;DR: Progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors, and on developing novel therapeutics that can facilitate and enhance lung repair.
Journal ArticleDOI
Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps
TL;DR: Neutrophil elastase escapes azurophilic granules, translocates to the nucleus, and degrades histones to promote chromatin decondensation necessary for NET formation.
References
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Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood
Stephen Clark,Adrienne C. Ma,Samantha A. Tavener,Braedon McDonald,Zahra Goodarzi,Margaret M. Kelly,Kamala D. Patel,Subhadeep Chakrabarti,Erin F. McAvoy,Gary D. Sinclair,Elizabeth Keys,Emma Allen-Vercoe,Rebekah DeVinney,Christopher J. Doig,Francis H. Y. Green,Paul Kubes +15 more
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TL;DR: Standardized procedures for inducing sepsis in mice and rats are defined by applying defined severity grades of sepsi through modulation of the position of cecal ligation.
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