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p38-MAPK inhibition and endotoxin induced tubular dysfunction in men

2004; Maney Publishing; Volume: 10; Issue: 6 Linguagem: Inglês

10.1179/096805104225005869

1743-2839

Jan G. Zijlstra, Jaap E. Tulleken, Jack J. M. Ligtenberg, Peter de Boer, Tjip S. van der Werf,

Neutrophil, Myeloperoxidase and Oxidative Mechanisms

To evaluate the possibility of preventing endotoxin induced renal damage by p38-MAPK inhibition in a human model.Twenty-one healthy young male volunteers received 4 ng/kg Escherichia coli endotoxin as a single dose. Four groups of volunteers received an oral dose of placebo or 350, 700 or 1400 mg RWJ-67657, a p38-MAPK inhibitor, 20 min before endotoxin infusion. Urine samples were collected at set time intervals. The urinary excretion rate of beta(2)-microglobulin and N-acetyl-beta-D-glucosaminidase, as indicators of tubular dysfunction was determined.There was a significant increase of beta(2)-microglobulin and N-acetyl-beta-D-glucosaminidase urine excretion rate after endotoxin infusion in the placebo group. p38-MAPK inhibition prevented the increase of markers for tubulopathy.Endotoxin infusion induces measurable tubular damage. Blocking the p38-MAPK may prevent this damage. The mechanism is unclear, but blocking TNF-alpha release is a possible explanation.