>>Published online before print September 3, 2002
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.192222999
Medical Sciences
Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation
( tumor necrosis factor | NF-B | lipopolysaccharide )
Luis Ulloa *, Mahendar Ochani *, Huan Yang *, Mahira Tanovic *, Daniel Halperin *, Runkuan Yang , Christopher J. Czura *, Mitchell P. Fink , and Kevin J. Tracey *
*Laboratory of Biomedical Science, North Shore-LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030; and Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 616 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261
Edited by Anthony Cerami, The Kenneth S. Warren Institute, Kitchawan, NY, and approved July 10, 2002 (received for review April 12, 2002)
Sepsis, a potentially fatal clinical syndrome, is mediated by an early (e.g., tumor necrosis factor and IL-1) and late [e.g., high mobility group B-1 (HMGB1)] proinflammatory cytokine response to infection. Specifically targeting early mediators has not been effective clinically, in part because peak mediator activity often has passed before therapy can be initiated. Late-acting downstream effectors, such as HMGB1, that mediate sepsis lethality may be more relevant therapeutic targets. Ethyl pyruvate (EP) recently was identified as an experimental therapeutic that significantly protects against lethal hemorrhagic shock. Here, we report that EP attenuates lethal systemic inflammation caused by either endotoxemia or sepsis even if treatment begins after the early tumor necrosis factor response. Treatment with EP initiated 24 h after cecal puncture significantly increased survival (vehicle survival = 30% vs. EP survival = 88%, P < 0.005). EP treatment significantly reduced circulating levels of HMGB1 in animals with established endotoxemia or sepsis. In macrophage cultures, EP specifically inhibited activation of p38 mitogen-activated protein kinase and NF-B, two signaling pathways that are critical for cytokine release. This report describes a new strategy to pharmacologically inhibit HMGB1 release with a small molecule that is effective at clinically achievable concentrations. EP now warrants further evaluation as an experimental "rescue" therapeutic for sepsis and other potentially fatal systemic inflammatory disorders.<<
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