title: Treatment with p33 curtails morbidity and mortality in a histone-induced murine shock model.
abstract: 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.
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences, Biomedical Center, Lund, Lund, Sweden.
authors.forename: Johannes
authors.initials: J
authors.lastname: Westman
authors.forename: Emanuel
authors.initials: E
authors.lastname: Smeds
authors.forename: Linda
authors.initials: L
authors.lastname: Johansson
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Anders I
authors.initials: AI
authors.lastname: Olin
authors.forename: Erik
authors.initials: E
authors.lastname: Malmström
authors.forename: Adam
authors.initials: A
authors.lastname: Linder
authors.forename: Heiko
authors.initials: H
authors.lastname: Herwald
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000276:immunology / Q000473:pathology; D042783:Endothelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D006461:Hemolysis / Q000187:drug effects / Q000276:immunology; D006657:Histones / Q000633:toxicity*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D024101:Mitochondrial Proteins / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D012769:Shock / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control
chemical_list: C490193:C1qbp protein, mouse; D006657:Histones; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins