101. Endotoxin increases plasma soluble tumor necrosis factor-related apoptosis-inducing ligand level mediated by the p38 mitogen-activated protein kinase signaling pathway.
- Author
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Lub-de Hooge MN, de Jong S, Vermot-Desroches C, Tulleken JE, de Vries EG, and Zijlstra JG
- Subjects
- Adult, Apoptosis, Apoptosis Regulatory Proteins, Endotoxemia metabolism, Humans, Imidazoles pharmacology, Ligands, MAP Kinase Signaling System, Male, Pyridines pharmacology, TNF-Related Apoptosis-Inducing Ligand, Time Factors, Tumor Necrosis Factor-alpha metabolism, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors, Endotoxins metabolism, Membrane Glycoproteins blood, Signal Transduction, p38 Mitogen-Activated Protein Kinases metabolism
- Abstract
Despite extensive knowledge about the mechanisms behind sepsis, this syndrome still caries a large morbidity and mortality rate. Dysregulated immune and coagulation systems are held responsible. However, additional pathophysiological mechanisms such as uncontrolled apoptosis induced by death receptor ligands might well play a role. P38 mitogen-activated protein (MAP) kinase inhibitors are considered as potential drugs in inflammatory diseases. Therefore, the effect of endotoxin administration on the response of soluble(s) tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL), a death receptor ligand, and the role of p38 MAP kinase inhibition was studied in 21 human volunteers. The volunteers received 30 min before the endotoxin infusion a single oral dose of placebo or the selective p38 MAP kinase inhibitor drug, RWJ-67657. Plasma sTRAIL increased 10-fold to 6564 +/- 511 pg/mL after 2.5 h. This increase was blocked completely by the highest dose of RW-J6765. This is the first report showing that endotoxin increases sTRAIL where the p38 MAP kinase signaling pathway is involved.
- Published
- 2004
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