Extracellular histones are major mediators of death in sepsis.
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.
Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Jun
J
Xu
Xiaomei
X
Zhang
Rosana
R
Pelayo
Marc
M
Monestier
Concetta T
CT
Ammollo
Fabrizio
F
Semeraro
Fletcher B
FB
Taylor
Naomi L
NL
Esmon
Florea
F
Lupu
Charles T
CT
Esmon
D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D002417:Cattle; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004727:Endothelium / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D004926:Escherichia coli / Q000502:physiology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D006470:Hemorrhage / Q000209:etiology / Q000473:pathology; D006657:Histones / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D007674:Kidney Diseases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D010215:Papio; D011134:Polysaccharides / Q000009:adverse effects; D018805:Sepsis / Q000188:drug therapy / Q000209:etiology / Q000401:mortality* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects
D000906:Antibodies; D006657:Histones; D009842:Oligopeptides; D011134:Polysaccharides; D014409:Tumor Necrosis Factor-alpha; C047135:protein C activator peptide