Letter abstract
Nature Medicine 15, 1318 - 1321 (2009)
Published online: 25 October 2009 | doi:10.1038/nm.2053
Extracellular histones are major mediators of death in sepsis
Jun Xu1, Xiaomei Zhang2, Rosana Pelayo3, Marc Monestier4, Concetta T Ammollo1, Fabrizio Semeraro1, Fletcher B Taylor1, Naomi L Esmon1, Florea Lupu1 & Charles T Esmon1,2
Abstract
Hyperinflammatory responses can lead to a variety of diseases, including sepsis1. 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.
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
- Howard Hughes Medical Institute, Oklahoma City, Oklahoma, USA.
- Immunology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
- Temple Autoimmunity Center, Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Correspondence to: Charles T Esmon1,2 e-mail: esmonc@omrf.org
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