Inhibition of leucotriene B4 synthesis by BW 755c does not reduce polymorphonuclear leucocyte (PMNL) accumulation induced by monosodium urate crystals.
Monosodium urate (MSU) crystals induce an inflammatory response when injected into the rat subcutaneous air pouch, which is characterised by polymorphonuclear leucocyte (PMNL) accumulation and plasma leakage. The arachidonic acid metabolites leucotriene B4 (LTB4), prostaglandin E2 (PGE2), 6-oxo-prostaglandin F1 alpha, (6-oxo-PGF1 alpha), and thromboxane B2 (TXB2) are found in increased concentrations in MSU induced exudates compared with animals injected with phosphate buffered saline (PBS). Pretreatment of animals with BW 755c significantly reduced the concentration of both lipoxygenase and cyclo-oxygenase derived arachidonic acid metabolites. Although BW 755c reduced MSU crystal induced plasma leakage, it did not affect PMNL accumulation. Pretreatment of animals with indomethacin selectively inhibited the generation of cyclo-oxygenase derived arachidonic acid metabolites and reduced MSU crystal induced plasma leakage but had no effect on PMNL accumulation. The inhibition of plasma leakage by either BW 755c or indomethacin was reversed by prostaglandin E2 (1 microgram/ml), which itself produced a significant increase in plasma leakage. The injection of purified LTB4 (4 ng/ml or 40 ng/ml) did not induce either plasma leakage or PMNL accumulation within the air pouch. These data suggest that although MSU crystals stimulate LTB4 production, LTB4 is not the mediator of MSU crystal induced PMNL accumulation. Cyclo-oxygenase products of arachidonic acid metabolism (e.g., PGE2), however, appear to play a part in MSU crystal induced plasma leakage.
Forrest
M J
MJ
Department of Rheumatology, Royal North Shore Hospital of Sydney, St Leonards, NSW, Australia.
Zammit
V
V
Brooks
P M
PM
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015232:Dinoprostone; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D007958:Leukocyte Count / Q000187:drug effects; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008297:Male; D009504:Neutrophils / Q000187:drug effects*; D011458:Prostaglandins E / Q000494:pharmacology; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014527:Uric Acid
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011458:Prostaglandins E; D011459:Prostaglandins E, Synthetic; D011720:Pyrazoles; D007975:Leukotriene B4; D014527:Uric Acid; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D015232:Dinoprostone; D007213:Indomethacin