Abstract
IntroductionCell-free plasma hemoglobin is associated with poor outcome in patients with sepsis. Extracellular hemoglobin and secondarily released heme amplify inflammation in the presence of microbial TLR ligands and/or endogenous mediators. Hemopexin, a plasma protein that binds heme with extraordinary affinity, blocks these effects and has been proposed as a possible treatment approach to decrease inflammation in critically ill patients.MethodsWe studied mouse models of endotoxemia, burn wound infections and peritonitis in order to assess if a repletion strategy for hemopexin might be reasonable. We also measured hemopexin in small numbers of three patient populations that might be logical groups for hemopexin therapy: patients with sepsis and ARDS, patients with severe burns, and premature infants.ResultsDespite severe disease, mean plasma hemopexin levels were increased above baseline in each murine model. However, plasma hemopexin levels were decreased or markedly decreased in many patients in each of the three patient populations.ConclusionsPotentially different behavior of hemopexin in mice and humans may be important to consider when utilizing murine models to represent acute human inflammatory diseases in which heme plays a role. The findings raise the possibility that decreased hemopexin could result in insufficiently neutralized or cleared heme in some patients with ARDS, burns, or in premature infants who might be candidates to benefit from hemopexin administration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0885-x) contains supplementary material, which is available to authorized users.
Highlights
Cell-free plasma hemoglobin is associated with poor outcome in patients with sepsis
LPS induced the production of tumor necrosis factor (TNF), which was significantly enhanced by injection with LPS, as has been previously described [17]
In mice with severe infections (E. coli O4 107 cfu/mouse injected), Hx was increased by day 1 and remained above baseline despite high bacteremia and high levels of interleukin 6 (IL-6)
Summary
Cell-free plasma hemoglobin is associated with poor outcome in patients with sepsis. Extracellular hemoglobin and secondarily released heme amplify inflammation in the presence of microbial TLR ligands and/or endogenous mediators. A plasma protein that binds heme with extraordinary affinity, blocks these effects and has been proposed as a possible treatment approach to decrease inflammation in critically ill patients. In the presence of infection, extracellular hemoglobin and heme amplify inflammation by synergizing with microbial Toll-like receptor (TLR) agonists and non-microbial endogenous ligands, such as high-mobility group box 1 protein (HMGB1), to induce high levels of proinflammatory cytokines including tumor necrosis factor (TNF) and interleukin 6 (IL-6) [3,4,5]. Free hemoglobin is eliminated by binding to plasma protein haptoglobin and transported into cells of. Much less is known about levels of Hx in inflammation or infection
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