PHARMACOLOGICAL EVALUATION OF LEUKOTRIENE BIOSYNTHESIS AND INFLAMMATION IN AN ADOPTIVE MODEL OF PERITONEAL ANAPHYLAXIS IN THE MOUSE

The ability of IgE anti-arsenilate hapten-sensitized bone marrow-deriv ed mast cell line (1BD-8) to generate leukotriene C4 (LTC4) and increa se vascular permeability, and neutrophil infiltration in vivo in Balb/ c mice challenged with arsenilated BSA (ARS-BSA) was studied. Sensitiz ed 1BD8 cells (5-10 x 10(6)) were administered intraperitoneally follo wed by 0.1 mug ARS-BSA. Following CO2 asphyxia, the peritoneal content s were harvested and assayed for immunoreactive LTC4 (iLTC4) by radioi mmunoassay. Maximal production of iLTC4 (60 ng/mouse) was seen 2.5 min after challenge and then decreased to a nadir at 15 min. Animals whic h were depleted of resident peritoneal cells by treatment with cycloph osphamide gave an iLTC4 response equivalent to non-treated controls, i ndicating that the transferred cells contributed most of the iLTC4 res ponse. The oral administration of the 5-lipoxygenase (5-LO) inhibitors , phenidone, SK&F 107649, and the pyridinyl imidazoles SK&F 104493 and SK&F 105809 all reduced the iLTC4 response (61-96% inhibition); where as the vasoactive amine antagonist cyproheptadine and the cyclooxygena se inhibitors, meclofenamic acid and naproxen, had no effect. Extravas ation of Evans blue dye was also monitored spectrophotometrically and was significant 5 min after challenge and reached a plateau at 45 min. Like iLTC4, despite depletion of resident peritoneal cells, no differ ence in dye extravasation was seen in cyclophosphamide-versus saline-t reated animals. Those compounds which inhibited iLTC4 also inhibited d ye extravasation with similar potency. Cyproheptadine, however modestl y, inhibited dye extravasation (33%)-without altering iLTC4 production . Neutrophil infiltration was also monitored and was significantly inh ibited by the oral administration of phenidone (73%) and SK&F 104493 ( 81%). This model provides a reliable method to evaluate in vivo inhibi tion of leukotriene biosynthesis and the associated inflammatory respo nse induced by a pathophysiologically relevant stimulus. (C) 1993 Wile y-Liss, Inc.