Targeting high mobility group box 1 as a late-acting mediator of inflammation

Sepsis, a lethal systemic inflammatory response to infection, affects nearly 750,000 patients in the United States annually and has a mortality of 30%. Mounting evidence has implicated cytokines, circulating factors produced by the innate immune system, as critical mediators of sepsis-related tissue injury and death. Many resources have been expended to elucidate the pathologic mechanisms that underlie sepsis and to develop appropriate and effective therapeutics. To date, no antiinflammatory agent has been clinically approved for the treatment of sepsis because even a slight delay in administration of therapeutics that target inflammatory mediators renders most approaches ineffective. These and other findings, described in part in this review, suggest that successful clinical management of sepsis may be dependent on identification of late-acting, downstream lethal mediators that can be targeted in a broader therapeutic window. A candidate mediator of delayed lethality is high mobility group box 1, a cellular and nuclear protein that is now recognized as a cytokine and experimental therapeutic target.