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HMG-1 as a late mediator of endotoxin lethality in mice.

Science (New York, N.Y.)

pharmacology, Bacteremia, blood, Carrier Proteins, genetics, immunology, metabolism, toxicity, Cell Line, Cells, Cultured, Endotoxemia, Endotoxins, HMGB1 Protein, High Mobility Group Proteins, Humans, Animals, Immune Sera, Immunization, Passive, Interferon-gamma, Interleukin-1, Lethal Dose 50, Leukocytes, Mononuclear, Lipopolysaccharides, Macrophages, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, RNA, Messenger, Time Factors, Tumor Necrosis Factor-alpha

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      Abstract

      Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

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      10398600

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