Inhibition of p38 mitogen-activated protein kinase: Dose-dependent suppression of leukocyte and endothelial response after endotoxin challenge in humans

OBJECTIVE We studied the activity of a single oral dose of RWJ-67657, a synthetic p38 mitogen-activated protein kinase inhibitor, in preventing dual leukocyte/endothelial activation after endotoxin infusion in healthy volunteers. DESIGN Prospective placebo-controlled study. SETTING Intensive care unit at a university medical center. SUBJECTS Twenty-one healthy male volunteers. INTERVENTIONS Endotoxin (4 ng/kg) as a 1-min infusion. According to randomization, the volunteers received placebo (n = 6) or 1400 mg (n = 4), 700 mg (n = 6), or 350 mg (n = 5) of RWJ-67657. MEASUREMENTS AND MAIN RESULTS Neutrophil activation was investigated by analyzing the extent of membrane expression of adhesion markers by calibrated flow cytometry. Circulating intercellular adhesion molecule-1 and E-selectin were measured by enzyme-linked immunosorbent assays. The endotoxin-induced shedding of L-selectin was diminished in a dose-dependent manner (p < .0001). High-dose RWJ-67657 prevented up-regulation of the integrins CD11b (p < .01) and CD 66b (p < .01) on neutrophils. The endotoxin-induced increase in circulating intercellular adhesion molecule-1 and circulation E-selectin was almost completely prevented by high-dose RWJ-67657. CONCLUSION A single oral dose of RWJ-67657 prevented neutrophil and endothelial activation after endotoxin infusion.