Cellular and biochemical characterization of the anti-inflammatory effects of DuP 654 in the arachidonic acid murine skin inflammation model.
The possible utility of DuP 654, a potent 5-lipoxygenase inhibitor, for treating human inflammatory skin disease was investigated in murine skin treated with 1.0 mg arachidonic acid (AA). When DuP 654 was applied to murine skin treated with AA, it inhibited the resulting inflammation and influx of cells. High performance liquid chromatography and radioimmunoassay analysis of lipid extracts from AA-treated ears indicated that the influx of polymorphonuclear leukocytes (PMN) was temporally preceded by an appearance of significant amounts of 5-HETE (6.7 +/- 1.4 ng/ear) and Leukotriene B4 LTB4 0.92 +/- 0.2 ng/ear) when compared with extracts of untreated ears (5-HETE, 02 +/- 0.3 ng/ear; LTB4, less than 0.1 ng/ear). The levels of the 5-lipoxygenase products were reduced by treatment with 10 micrograms/ear DUP 654. Lipid extracts from AA-treated ears contain chemotactic activity for human PMN and this chemotactic activity in the AA-treated ears could be reduced but not eliminated by immunosorption with anti-LTB4 antibodies coupled to protein A-agarose. The appearance of the chemotactic activity was inhibited by DuP 654. Taken together, these data suggest that DuP 654 may have utility in human inflammatory skin disease.
Harris
R R
RR
Medical Products Department, E.I. du Pont de Nemours and Company, Wilmington, Del.
Mackin
W M
WM
Batt
D G
DG
Rakich
S M
SM
Collins
R J
RJ
Bruin
E M
EM
Ackerman
N R
NR
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D002633:Chemotaxis / Q000187:drug effects; D003872:Dermatitis / Q000188:drug therapy* / Q000503:physiopathology; D004487:Edema / Q000139:chemically induced / Q000503:physiopathology; D004578:Electron Spin Resonance Spectroscopy; D007213:Indomethacin / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects; D050356:Lipid Metabolism; D016859:Lipoxygenase Inhibitors; D008297:Male; D008691:Methadone / Q000494:pharmacology; D051379:Mice; D009284:Naphthols / Q000494:pharmacology*; D009195:Peroxidase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D016859:Lipoxygenase Inhibitors; D009284:Naphthols; D016718:Arachidonic Acid; C061316:2-(phenylmethyl)-1-naphthol; D009195:Peroxidase; D001091:Arachidonate Lipoxygenases; D008691:Methadone; D007213:Indomethacin