The role of high mobility group box-1 protein in severe sepsis

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Abstract
Despite medical advances, mortality in severe sepsis remains high. As our understanding of the innate immune system has expanded, clinical trials have focused on inhibiting cytokines present early in the infectious process such as interleukin-1 and tumor necrosis factor-alpha, although with disappointing results. There is evidence that the nuclear protein high mobility group box-1 protein, when released extracellularly, acts as a persistent mediator of sepsis and is therefore a promising candidate for therapeutic intervention. This review summarizes current knowledge of the protein and highlights recent relevant findings. High mobility group box-1 protein may be released into the circulation either due to necrosis of cells or by active release from macrophages and endothelial cells. Models of experimental sepsis in mice have shown a strong association between extracellular high mobility group box-1 protein and lethality. Treatments against the biological activities of high mobility group box-1 protein reduce lethality in these models. Other studies have shown high mobility group box-1 protein as a key regulator in acute and chronic inflammation. Recent findings confirm that high mobility group box-1 protein is persistently elevated in human patients with severe sepsis. Despite all efforts, mortality in severe sepsis remains high. A massive amount of evidence indicates high mobility group box-1 protein as a delayed and important propagator of inflammation. Recent studies confirm persisting high levels of high mobility group box-1 protein in serum up to 1 week after hospitalization. Reducing levels of the protein by anti-high mobility group box-1 protein treatment may be one way to moderate uncontrolled inflammation seen in sepsis.