Journal
JOURNAL OF INNATE IMMUNITY
Volume 6, Issue 6, Pages 819-830Publisher
KARGER
DOI: 10.1159/000363348
Keywords
Extracellular histones; Antimicrobial peptides; Host defense; Immune response; Septic shock
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Funding
- foundation of Alfred Osterlund
- foundation of Crafoord
- foundation of Greta and Johan Kock
- Knut and Alice Wallenberg Foundation
- Ragnar Soderberg Foundation
- Sten K Johnson
- Sven-Olof Janson Life-work
- Medical Faculty at Lund University
- Swedish Foundation for Strategic Research
- Swedish Research Council
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Collateral damage caused by extracellular histones has an immediate impact on morbidity and mortality in many disease models. A significant increase in the levels of extracellular histones is seen in critically ill patients with trauma and sepsis. We showed that histones are released from necrotic cells in patients with invasive skin infections. Under in vitro conditions, endogenous p33, an endothelial surface protein also known as the gC1q receptor, interacts with histones released from damaged endothelial cells. Functional analyses have revealed that recombinantly expressed p33 completely neutralizes the harmful features of histones, i.e. hemolysis of erythrocytes, lysis of endothelial cells and platelet aggregation. We also noted that mice treated with a sublethal dose of histones developed severe signs of hemolysis, thrombocytopenia and lung tissue damage already 10 min after inoculation. These complications were fully counteracted when p33 was administered together with the histones. Moreover, application of p33 significantly improved survival in mice receiving an otherwise lethal dose of histones. Together, our data suggest that treatment with p33 is a promising therapeutic approach in severe infectious diseases. (C) 2014 S. Karger AG, Basel
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