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

2002; Lippincott Williams & Wilkins; Volume: 30; Issue: 4 Linguagem: Inglês

10.1097/00003246-200204000-00021

1530-0293

J. W. Fijen, Jaap E. Tulleken, Anneke C. Muller Kobold, Peter de Boer, Tjip S. van der Werf, Jack J. M. Ligtenberg, Rob Spanjersberg, Jan G. Zijlstra,

Neutrophil, Myeloperoxidase and Oxidative Mechanisms

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.