Research ArticleSepsis

A Central Role for Free Heme in the Pathogenesis of Severe Sepsis

Science Translational Medicine  29 Sep 2010:
Vol. 2, Issue 51, pp. 51ra71
DOI: 10.1126/scitranslmed.3001118

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Casting Heme in a New Light

Sepsis, or severe systemic infection, is a deadly disease that has always been difficult to treat. Despite modern-day antibiotics and intensive care management, patients with sepsis still have a high rate of major complications and death. These severe consequences are thought to be a result of simultaneous overwhelming infection and an overexuberant immune response, which together damage tissues and lead to organ dysfunction. One cell type that is injured during sepsis is the erythrocyte. As these red blood cells lyse, hemoglobin is released and oxidized, releasing free heme into the circulation. This heme is not an innocent bystander, however, as Larsen et al. now report. It increases inflammation and cell death, exacerbating the damage to the body and increasing the risk of death.

The authors found that mice lacking heme oxygenase 1, the enzyme that breaks down heme into harmless by-products, have more free circulating heme, which makes them more susceptible to death from sepsis than are matching wild-type mice. In addition, giving extra heme to wild-type mice suffering from sepsis greatly increases their risk of organ dysfunction and death without affecting the number of bacteria in their blood. Moreover, hemopexin, a protein produced by the body to scavenge free heme, protects mice and human patients with sepsis from the deleterious effects of heme and decreases the risk of complications and death.

Because these authors have shown that heme concentrations are associated with worse prognosis in sepsis patients, we may now have a new way to monitor patients’ health status and, eventually, to treat them. Measurements of heme and hemopexin in patients with sepsis may predict who needs more intensive interventions, potentially allowing for more timely treatment before organ failure ensues. In addition, high-risk patients could be given extra hemopexin or other heme-neutralizing substances to possibly save them from death caused by sepsis, even when all the current treatments fail.

Footnotes

  • * Present address: Universidade Federal do Rio de Janeiro Campus Macaé–Instituto Macaé de Metrologia e Tecnologia, Macaé, Rio de Janeiro 27930-560, Brazil.

  • Citation: R. Larsen, R. Gozzelino, V. Jeney, L. Tokaji, F. A. Bozza, A. M. Japiassú, D. Bonaparte, M. M. Cavalcante, Â. Chora, A. Ferreira, I. Marguti, S. Cardoso, N. Sepúlveda, A. Smith, M. P. Soares, A central role for free heme in the pathogenesis of severe sepsis. Sci. Transl. Med. 2, 51ra71 (2010).