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

Heme from red blood cells released in septic shock worsens organ dysfunction and increases the risk of death, but can be overcome by a scavenger of free heme. 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. 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.