Anaphylactic challenge causes eosinophil accumulation in bronchoalveolar lavage fluid of guinea pigs. Modulation by betamethasone, phenidone, indomethacin, WEB 2086, and a novel antiallergy agent, SCH 37224.
Eosinophil infiltration into bronchoalveolar areas of the lung has been assessed in guinea pigs sensitized to ovalbumin (OA) and then challenged with the aerosolized antigen. Cell content, histamine, and guinea pig albumin (GPA) have been measured in bronchoalveolar lavage (BAL) fluid from these animals. Extensive eosinophil accumulation resulted from sensitization followed by OA challenge; monocytes that initially accounted for greater than 80% of the BAL cells remained essentially constant, and neutrophils comprised less than 3% of the population throughout. Eosinophils were elevated at 3 h, peaked with a fivefold increase at 24 h, and remained elevated for at least 7 days. Histopathologic changes observed in lungs taken from sensitized guinea pigs 24 h after OA challenge confirm this eosinophilia. Increased histamine and GPA were detected only at 5 min. Oral treatment with betamethasone (ED50 = 0.4 mg/kg), phenidone (ED50 = 15 mg/kg), Sch 37224 (ED50 = 0.5 mg/kg), and WEB 2086 (ED50 = 4 mg/kg) decreased eosinophil accumulation in the BAL fluid, indicating roles for 5-lipoxygenase products and PAF in this multimediator-dependent model of allergic inflammation. On the other hand, 4 mg/kg of indomethacin increased total cells with no effect on eosinophils, precluding a major role for cyclooxygenase products. Sch 37224, an antileukotriene agent and an orally active novel antiallergy agent in sheep, guinea pigs, and humans, is as potent as betamethasone at blocking eosinophil infiltration, suggesting that it may also suppress human pulmonary inflammation.
Gulbenkian
A R
AR
Department of Allergy and Inflammation, Schering-Plough Research, Bloomfield, NJ 07003.
Fernandez
X
X
Kreutner
W
W
Minnicozzi
M
M
Watnick
A S
AS
Kung
T
T
Egan
R W
RW
D000418:Albumins / Q000032:analysis; D000707:Anaphylaxis / Q000209:etiology / Q000473:pathology*; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000473:pathology; D001381:Azepines / Q000494:pharmacology; D001623:Betamethasone / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000032:analysis / Q000166:cytology*; D002452:Cell Count / Q000187:drug effects; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects*; D006168:Guinea Pigs; D006632:Histamine / Q000032:analysis; D007114:Immunization; D007213:Indomethacin / Q000494:pharmacology; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000473:pathology; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D013931:Thromboxanes / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology
D000418:Albumins; D001381:Azepines; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D009287:Naphthyridines; D010972:Platelet Activating Factor; D011720:Pyrazoles; D013931:Thromboxanes; D014230:Triazoles; C052518:WEB 2086; C058078:Sch 37224; D006632:Histamine; D010047:Ovalbumin; D001623:Betamethasone; C015429:phenidone; D007213:Indomethacin