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-α, 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-α1-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.

The inherited deficiency of adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4) activity in humans is associated with an immunodeficiency. Some of the immunodeficient and enzyme-deficient patients respond immunologically to periodic infusions of irradiated erythrocytes containing adenosine deaminase. It has been previously reported that erythrocytes and lymphocytes from immunodeficient and enzyme-deficient children contained increased concentrations of ATP, and in the one child studied after erythrocyte infusion therapy, the intracellular level of ATP detoxifies adenosine by converting it to inosine (10). The hypotheses then differ in their proposed mechanisms by which adenosine exerts its cytotoxic effects in cells incapable of eliminating this purine nucleoside. It has been proposed that cyclic AMP mediates the cytotoxic effects of adenosine (11,19), that the accumulated nucleotides of adenosine induce a pyrimidine nucleotide starvation (10, 12) or inhibit glycolysis (5), and that adenosine combines intracellularly with homocysteine to form S-adenosylhomocysteine, which in turn acts as a potent inhibitor of methylation reactions, including the methylation of newly synthesized DNA (20).There are specific objections to most of these proposals. In a model system, Ullman et al. (12) We have observed very abnormal levels of 2'-deoxyadenosine triphosphate (dATP) in the erythrocytes of immunodeficient, adenosine deaminase-deficient patients but not in the erythrocytes of an immunocompetent, adenosine deaminase-deficient patient. Furthermore, we have followed the loss of erythrocyte dATP in two unrelated adenosine deaminasedeficient, immunodeficient patients after the infusion of erythrocytes containing the missing enzyme activity.f To whom reprint requests should be addressed

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