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 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.
Lub-de Hooge
Marjolin N
MN
Department of Hospital Pharmacy, Groningen University Hospital, The Netherlands.
de Jong
Steven
S
Vermot-Desroches
Claudine
C
Tulleken
Jaap E
JE
de Vries
Elisabeth G E
EG
Zijlstra
Jan G
JG
D000328:Adult; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D019446:Endotoxemia / Q000378:metabolism; D004731:Endotoxins / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008024:Ligands; D020935:MAP Kinase Signaling System; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D004731:Endotoxins; D007093:Imidazoles; D008024:Ligands; D008562:Membrane Glycoproteins; D011725:Pyridines; C400277:RWJ 67657; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases