p38-MAPK inhibition and endotoxin induced tubular dysfunction in men

Background: To evaluate the possibility of preventing endotoxin induced renal damage by p38-MAPK inhibition in a human model. Design and Methods: 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. Results: 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. Conclusions: 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.