Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation.
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-kappaB, 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.
Laboratory of Biomedical Science, North Shore-LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030, USA.
Luis
L
Ulloa
Mahendar
M
Ochani
Huan
H
Yang
Mahira
M
Tanovic
Daniel
D
Halperin
Runkuan
R
Yang
Christopher J
CJ
Czura
Mitchell P
MP
Fink
Kevin J
KJ
Tracey
D000818:Animals; D002460:Cell Line; D019446:Endotoxemia / Q000150:complications; D004789:Enzyme Activation / Q000187:drug effects; D024243:HMGB1 Protein / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011773:Pyruvates / Q000008:administration & dosage / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000150:complications; D015398:Signal Transduction / Q000187:drug effects; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011773:Pyruvates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C046522:ethyl pyruvate; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases