Extracellular histones are major mediators of death in sepsis

• Published in: Nature medicine Vol. 15; no. 11; pp. 1318 - 1321
• Main Authors: Esmon, Charles T, Xu, Jun, Zhang, Xiaomei, Pelayo, Rosana, Monestier, Marc, Ammollo, Concetta T, Semeraro, Fabrizio, Taylor, Fletcher B, Esmon, Naomi L, Lupu, Florea
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-11-2009; Nature Publishing Group
• Subjects: Animals; Antibodies - pharmacology; Antibodies - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cattle; Cell Line, Transformed; Cytotoxicity; Disease Models, Animal; E coli; Endothelium - drug effects; Endothelium - pathology; Endothelium - ultrastructure; Escherichia coli; Escherichia coli - physiology; Extracellular Fluid - drug effects; Extracellular Fluid - metabolism; Flow Cytometry; Health aspects; Hemorrhage - etiology; Hemorrhage - pathology; Histones; Histones - drug effects; Histones - immunology; Histones - metabolism; Histones - pharmacology; Infections; Infectious Diseases; Inflammatory diseases; Kidney Diseases - metabolism; letter; Macrophages - drug effects; Macrophages - metabolism; Macrophages - ultrastructure; Metabolic Diseases; Mice; Microscopy, Electron, Transmission - methods; Molecular biology; Molecular Medicine; Mortality; Neurosciences; Neutrophils - drug effects; Neutrophils - pathology; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Papio; Patient outcomes; Polysaccharides - adverse effects; Proteins; Renal function; Sepsis; Sepsis - drug therapy; Sepsis - etiology; Sepsis - mortality; Sepsis - pathology; Thromboembolism; Tumor Necrosis Factor-alpha - adverse effects; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2053

Extracellular histones released in response to inflammatory challenge contribute to organ failure and death during sepsis. Histone-specific antibodies and activated protein C had beneficial effects in animal models of sepsis, pointing to extracellular histones as therapeutics targets for sepsis and other inflammatory conditions (
pages 1245–1246
).
Hyperinflammatory responses can lead to a variety of diseases, including sepsis
1
. 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.