A central role for free heme in the pathogenesis of severe sepsis.
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.
Larsen
Rasmus
R
Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
Gozzelino
Raffaella
R
Jeney
Viktória
V
Tokaji
László
L
Bozza
Fernando A
FA
Japiassú
André M
AM
Bonaparte
Dolores
D
Cavalcante
Moisés Marinho
MM
Chora
Angelo
A
Ferreira
Ana
A
Marguti
Ivo
I
Cardoso
Sílvia
S
Sepúlveda
Nuno
N
Smith
Ann
A
Soares
Miguel P
MP
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
D024243:HMGB1 Protein; D006418:Heme; D006466:Hemopexin; D051547:Heme Oxygenase-1