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* Laboratory of Experimental Internal Medicine and
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;
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877; and
¶ Boehringer Ingelheim Pharma KG, Biberach, Germany
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-
,
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-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.
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