title: Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis.
abstract: Extracellular histones are considered to be major mediators of death in sepsis. Although sepsis is a condition that may benefit from low-dose heparin administration, medical doctors need to take into consideration the potential bleeding risk in sepsis patients who are already at increased risk of bleeding due to a consumption coagulopathy. Here, we show that mechanisms that are independent of the anticoagulant properties of heparin may contribute to the observed beneficial effects of heparin in the treatment of sepsis patients. We show that nonanticoagulant heparin, purified from clinical grade heparin, binds histones and prevents histone-mediated cytotoxicity in vitro and reduces mortality from sterile inflammation and sepsis in mouse models without increasing the risk of bleeding. Our results demonstrate that administration of nonanticoagulant heparin is a novel and promising approach that may be further developed to treat patients suffering from sepsis.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands;
authors.forename: Karin C A A
authors.initials: KC
authors.lastname: Wildhagen
authors.forename: Pablo
authors.initials: P
authors.lastname: García de Frutos
authors.forename: Chris P
authors.initials: CP
authors.lastname: Reutelingsperger
authors.forename: Roy
authors.initials: R
authors.lastname: Schrijver
authors.forename: Cristina
authors.initials: C
authors.lastname: Aresté
authors.forename: Almudena
authors.initials: A
authors.lastname: Ortega-Gómez
authors.forename: Niko M
authors.initials: NM
authors.lastname: Deckers
authors.forename: H Coenraad
authors.initials: HC
authors.lastname: Hemker
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.forename: Gerry A F
authors.initials: GA
authors.lastname: Nicolaes
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry; D002478:Cells, Cultured; D005591:Chemical Fractionation; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006657:Histones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality*; D016019:Survival Analysis
chemical_list: D000925:Anticoagulants; D006657:Histones; D008070:Lipopolysaccharides; D006493:Heparin