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.


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.
Zijlstra
Jan G
JG
Intensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
Tulleken
Jaap E
JE
Ligtenberg
Jack J M
JJ
de Boer
Peter
P
van der Werf
Tjip S
TS
D000328:Adult; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000008:administration & dosage*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007684:Kidney Tubules / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D001613:beta 2-Microglobulin / Q000652:urine; D048828:beta-N-Acetyl-Galactosaminidase / Q000652:urine
D004731:Endotoxins; D007093:Imidazoles; D011725:Pyridines; C400277:RWJ 67657; D001613:beta 2-Microglobulin; C044101:endotoxin, Escherichia coli; D020928:Mitogen-Activated Protein Kinases; D048828:beta-N-Acetyl-Galactosaminidase