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Prepublished online as a Blood First Edition Paper on February 6, 2003; DOI 10.1182/blood-2002-11-3338.
Submitted November 5, 2002
Accepted January 27, 2003
Inhibition of coagulation, fibrinolysis and endothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during human endotoxemia
Judith Branger*, Bernt van den Blink, Sebastiaan Weijer, Abhya Gupta, Sander J H van Deventer, C Erik Hack, Maikel P Peppelenbosch, and Tom van der Poll
Laboratory of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
CLB and Laboratory for Clinical and Experimental Immunology, University of Amsterdam, Amsterdam, The Netherlands
Boehringer Ingelheim Pharma KG, Biberach, Germany
* Corresponding author; email: J.Branger{at}amc.uva.nl.
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- 2-antiplasmin complexes, plasminogen activator inhibitor type I), 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.
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