A central role for free heme in the pathogenesis of severe sepsis

Rasmus Larsen, Raffaella Gozzelino, Viktória Jeney, László Tokaji, Fernando A. Bozza, André M. Japiassú, Dolores Bonaparte, Moisés Marinho Cavalcante, Ângelo Chora, Ana Ferreira, Ivo Marguti, Sílvia Cardoso, Nuno Sepúlveda, Ann Smith, Miguel P. Soares

Research output: Contribution to journalArticle

245 Citations (Scopus)

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 hemecatabolizing 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.

Original languageEnglish
Article number51ra71
JournalScience Translational Medicine
Volume2
Issue number51
DOIs
Publication statusPublished - Sep 29 2010

    Fingerprint

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Larsen, R., Gozzelino, R., Jeney, V., Tokaji, L., Bozza, F. A., Japiassú, A. M., Bonaparte, D., Cavalcante, M. M., Chora, Â., Ferreira, A., Marguti, I., Cardoso, S., Sepúlveda, N., Smith, A., & Soares, M. P. (2010). A central role for free heme in the pathogenesis of severe sepsis. Science Translational Medicine, 2(51), [51ra71]. https://doi.org/10.1126/scitranslmed.3001118