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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‐derived mast cell line (1BD‐8) to generate leukotriene C4 (LTC4) and increase vascular permeability, and neutrophil infiltration in vivo in Balb/c mice challenged with arsenilated BSA (ARS‐BSA) was studied. Sensitized 1BD8 cells (5‐10 × 106) were administered intraperitoneally followed by 0.1 μg ARS‐BSA. Following CO2 asphyxia, the peritoneal contents were harvested and assayed for immunoreactive LTC4 (iLTC4) by radioimmunoassay. Maximal production of iLTC4 (60 ng/mouse) was seen 2.5 min after challenge and then decreased to a nadir at 15 min. Animals which were depleted of resident peritoneal cells by treatment with cyclophosphamide gave an iLTC4 response equivalent to non‐treated controls, indicating that the transferred cells contributed most of the iLTC4 response. 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); whereas the vasoactive amine antagonist cyproheptadine and the cyclooxygenase inhibitors, meclofenamic acid and naproxen, had no effect. Extravasation 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 difference in dye extravasation was seen in cyclophosphamide‐ versus saline‐treated animals. Those compounds which inhibited iLTC4 also inhibited dye extravasation with similar potency. Cyproheptadine, however modestly, inhibited dye extravasation (33%) without altering iLTC4 production. Neutrophil infiltration was also monitored and was significantly inhibited by the oral administration of phenidone (73%) and SK&F 104493 (81%). This model provides a reliable method to evaluate in vivo inhibition of leukotriene biosynthesis and the associated inflammatory response induced by a pathophysiologically relevant stimulus. © 1993 wiley‐Liss, Inc.