title: A central role for free heme in the pathogenesis of severe sepsis.
abstract: Low-grade polymicrobial infection induced by cecal ligation and puncture is lethal in heme oxygenase-1-deficient mice (Hmox1(-/-)), but not in wild-type (Hmox1(+/+)) mice. Here we demonstrate that the protective effect of this heme-catabolizing enzyme relies on its ability to prevent tissue damage caused by the circulating free heme released from hemoglobin during infection. Heme administration after low-grade infection in mice promoted tissue damage and severe sepsis. Free heme contributed to the pathogenesis of severe sepsis irrespective of pathogen load, revealing that it compromised host tolerance to infection. Development of lethal forms of severe sepsis after high-grade infection was associated with reduced serum concentrations of the heme sequestering protein hemopexin (HPX), whereas HPX administration after high-grade infection prevented tissue damage and lethality. Finally, the lethal outcome of septic shock in patients was also associated with reduced HPX serum concentrations. We propose that targeting free heme by HPX might be used therapeutically to treat severe sepsis.
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Larsen
authors.forename: Raffaella
authors.initials: R
authors.lastname: Gozzelino
authors.forename: Viktória
authors.initials: V
authors.lastname: Jeney
authors.forename: László
authors.initials: L
authors.lastname: Tokaji
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Bozza
authors.forename: André M
authors.initials: AM
authors.lastname: Japiassú
authors.forename: Dolores
authors.initials: D
authors.lastname: Bonaparte
authors.forename: Moisés Marinho
authors.initials: MM
authors.lastname: Cavalcante
authors.forename: Angelo
authors.initials: A
authors.lastname: Chora
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreira
authors.forename: Ivo
authors.initials: I
authors.lastname: Marguti
authors.forename: Sílvia
authors.initials: S
authors.lastname: Cardoso
authors.forename: Nuno
authors.initials: N
authors.lastname: Sepúlveda
authors.forename: Ann
authors.initials: A
authors.lastname: Smith
authors.forename: Miguel P
authors.initials: MP
authors.lastname: Soares
mesh_terms: D000818:Animals; D017209:Apoptosis; D001424:Bacterial Infections / Q000201:enzymology / Q000276:immunology; D024243:HMGB1 Protein / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006466:Hemopexin / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D051379:Mice; D008954:Models, Biological; D010084:Oxidation-Reduction; D018805:Sepsis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D024243:HMGB1 Protein; D006418:Heme; D006466:Hemopexin; D051547:Heme Oxygenase-1