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

JW Fijen*, JE Tulleken, ACM Kobold, P de Boer, TS van der Werf, JJM Ligtenberg, R Spanjersberg, JG Zijlstra

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)841-845
Number of pages5
JournalCritical Care Medicine
Issue number4
Publication statusPublished - Apr-2002
Event13th Annual Congress of the European-Society-of-Intensive-Care-Medicine - ROME, Italy
Duration: 1-Oct-20004-Oct-2000


  • adhesion molecules
  • endotoxin
  • leukocyte activation
  • p38 mitogen-activated protein kinase
  • sepsis
  • human
  • CD11B/CD18

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