Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species.
OBJECTIVE
Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) is promising for the treatment of inflammatory disorders, however, the efficacy of p38 MAPK inhibitors in clinical trials is limited so far. Since functional sensitivity of p38 MAPK is commonly predicted by preclinical species, we systematically investigated interspecies differences including human tissue.


METHODS
Ex vivo test models were established using whole blood and primary cells from different species such as mice, rats, pigs and humans to compare LPS-induced TNF-α inhibition of four different p38 MAPK reference inhibitors SB 203580, BIRB-796, Pamapimod, and a Losmapimod analogue as well as a proprietary imidazole-based p38 MAPK Inhibitor.


RESULTS
All analysed p38 MAPK inhibitors resulted in significant inhibition of LPS-induced TNF-α release but with high interspecies differences for dose sensitivity. IC50 values from human whole blood and PBMC showed significant higher sensitivity towards p38 MAPK inhibition compared with data from pig and rat.


CONCLUSIONS
Inhibition of TNF-α release by p38 MAPK inhibitors can be reliably identified in well-established laboratory species such as rat or mouse. However, our data indicate that animal models appear to be limited for valid prediction of the inhibitory potential for TNF-α release in humans. Thus, human tissues should be considered early in the drug development process of p38 MAPK inhibitors.
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University Tuebingen, Tuebingen, Germany.
Sarah
S
Fehr
Anke
A
Unger
Elke
E
Schaeffeler
Sonja
S
Herrmann
Stefan
S
Laufer
Matthias
M
Schwab
Wofgang
W
Albrecht
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011917:Rats, Inbred Lew; D013045:Species Specificity; D034421:Sus scrofa; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases