title: Inhibition of coagulation, fibrinolysis, and endothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during human endotoxemia.
abstract: 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.
authors.affiliation: Department of Infectious Disease, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. j.branger@amc.uva.nl
authors.forename: Judith
authors.initials: J
authors.lastname: Branger
authors.forename: Bernt
authors.initials: B
authors.lastname: van den Blink
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Weijer
authors.forename: Abhya
authors.initials: A
authors.lastname: Gupta
authors.forename: Sander J H
authors.initials: SJ
authors.lastname: van Deventer
authors.forename: C Erik
authors.initials: CE
authors.lastname: Hack
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: 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
chemical_list: 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