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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.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Larsen R,Gozzelino R,Jeney V,Tokaji L,Bozza FA,Japiassú AM,Bonaparte D,Cavalcante MM,Chora A,Ferreira A,Marguti I,Cardoso S,Sepúlveda N,Smith A,Soares MP

doi

10.1126/scitranslmed.3001118

subject

Has Abstract

pub_date

2010-09-29 00:00:00

pages

51ra71

issue

51

eissn

1946-6234

issn

1946-6242

pii

2/51/51ra71

journal_volume

2

pub_type

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