Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia.
The p38 mitogen-activated protein kinase (MAPK) participates in intracellular signaling cascades resulting in inflammatory responses. Therefore, inhibition of the p38 MAPK pathway may form the basis of a new strategy for treatment of inflammatory diseases. However, p38 MAPK activation during systemic inflammation in humans has not yet been shown, and its functional significance in vivo remains unclear. Hence, we exposed 24 healthy male subjects to an i.v. dose of LPS (4 ng/kg), preceded 3 h earlier by orally administered 600 or 50 mg BIRB 796 BS (an in vitro p38 MAPK inhibitor) or placebo. Both doses of BIRB 796 BS significantly inhibited LPS-induced p38 MAPK activation in the leukocyte fraction of the volunteers. Cytokine production (TNF-alpha, IL-6, IL-10, and IL-1R antagonist) was strongly inhibited by both low and high dose p38 MAPK inhibitor. In addition, p38 MAPK inhibition diminished leukocyte responses, including neutrophilia, release of elastase-alpha(1)-antitrypsin complexes, and up-regulation of CD11b with down-regulation of L-selectin. Finally, blocking p38 MAPK decreased C-reactive protein release. These data identify p38 MAPK as a principal mediator of the inflammatory response to LPS in humans. Furthermore, the anti-inflammatory potential of an oral p38 MAPK inhibitor in humans in vivo suggests that p38 MAPK inhibitors may provide a new therapeutic option in the treatment of inflammatory diseases.
Branger
Judith
J
Department of Infectious Diseases, Tropical Medicine, and AIDS, Academic Medical Center, and CLB and Laboratory for Clinical and Experimental Immunology, University of Amsterdam, Amsterdam, The Netherlands. j.branger@amc.uva.nl
van den Blink
Bernt
B
Weijer
Sebastiaan
S
Madwed
Jeffrey
J
Bos
Carina L
CL
Gupta
Abhya
A
Yong
Chan-Loi
CL
Polmar
Stephen H
SH
Olszyna
Dariusz P
DP
Hack
C Erik
CE
van Deventer
Sander J H
SJ
Peppelenbosch
Maikel P
MP
van der Poll
Tom
T
D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004311:Double-Blind Method; D019446:Endotoxemia / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases; D010671:Phenylurea Compounds
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002097:C-Reactive Protein; D016207:Cytokines; 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