Endotoxin increases plasma soluble tumor necrosis factor-related apoptosis-inducing ligand level mediated by the p38 mitogen-activated protein kinase signaling pathway

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 recepto...

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Bibliographic Details
Published in:Shock (Augusta, Ga.) Ga.), 2004-08, Vol.22 (2), p.186-188
Main Authors: LUB-DE HOOGE, Marjolin N, DE JONG, Steven, VERMOT-DESROCHES, Claudine, TULLEKEN, Jaap E, DE VRIES, Elisabeth G. E, ZIJLSTRA, Jan G
Format: Article
Language:English
Subjects:
Adult
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Apoptosis
Apoptosis Regulatory Proteins
Biological and medical sciences
Endotoxemia - metabolism
Endotoxins - metabolism
Humans
Imidazoles - pharmacology
Intensive care medicine
Ligands
Male
MAP Kinase Signaling System
Medical sciences
Membrane Glycoproteins - blood
p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases - metabolism
Pyridines - pharmacology
Signal Transduction
Time Factors
TNF-Related Apoptosis-Inducing Ligand
Tumor Necrosis Factor-alpha - metabolism
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Summary: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.
ISSN:1073-2322
1540-0514
DOI:10.1097/01.shk.0000132486.82177.ec