Inhibition of coagulation, fibrinolysis, and endothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during human endotoxemia.
P38 mitogen-activated protein kinase (MAPK) is an important component of intracellular signaling cascades that initiate various inflammatory cellular responses. To determine the role of p38 MAPK in the procoagulant response to lipopolysaccharide (LPS), 24 healthy subjects were exposed to an intravenous dose of LPS (4 ng/kg), preceded 3 hours earlier by orally administered 600 or 50 mg BIRB 796 BS (a specific p38 MAPK inhibitor), or placebo. The 600-mg dose of BIRB 796 BS strongly inhibited LPS-induced coagulation activation, as measured by plasma concentrations of the prothrombin fragment F1 + 2. BIRB 796 BS also dose dependently attenuated the activation and subsequent inhibition of the fibrinolytic system (plasma tissue-type plasminogen activator, plasmin-alpha2-antiplasmin complexes, and plasminogen activator inhibitor type 1) and endothelial cell activation (plasma soluble E-selectin and von Willebrand factor). Activation of p38 MAPK plays an important role in the procoagulant and endothelial cell response after in vivo exposure to LPS.
Branger
Judith
J
Department of Infectious Disease, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. j.branger@amc.uva.nl
van den Blink
Bernt
B
Weijer
Sebastiaan
S
Gupta
Abhya
A
van Deventer
Sander J H
SJ
Hack
C Erik
CE
Peppelenbosch
Maikel P
MP
van der Poll
Tom
T
D000328:Adult; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects*; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019446:Endotoxemia / Q000097:blood* / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases; D010671:Phenylurea Compounds
D015415:Biomarkers; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D009281:Naphthalenes; D011720:Pyrazoles; D048051:p38 Mitogen-Activated Protein Kinases; C452139:doramapimod; D010671:Phenylurea Compounds