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Cited by 1,539

The DOI matches its Crossref record; 19 of the 19 references it cites were found in a registry or an index.

Extracellular histones are major mediators of death in sepsis

Open access
Xu, Jun, Zhang, Xiaomei, Pelayo, Rosana, Monestier, Marc, Ammollo, Concetta T, Semeraro, Fabrizio, Taylor, Fletcher B, Esmon, Naomi L, Lupu, Florea, Esmon, Charles T·2009·Nature Medicine
DOI 10.1038/nm.2053
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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.

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Crossref · 10.1038/nm.2053

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Metadata

Authors
Xu, J., Zhang, X., Pelayo, R., Monestier, M., Ammollo, C. T., Semeraro, F., Taylor, F. B., Esmon, N. L., Lupu, F., & Esmon, C. T.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2009-10-25
Volume
15
Issue
11
Pages
1318-1321
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.2053
OpenAlex
W1978508787
Cited by
1,539
References
19
FWCI
32.49
Type
journal article
Language
en
Open access
green

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