Effect of the selective leukotriene B4 antagonist U-75302 on antigen-induced bronchopulmonary eosinophilia in sensitized guinea pigs.
The selective leukotriene B4 (LTB4) antagonist, U-75302, 6-(6-(3-hydroxy-1E,5Z-undecadien-1-yl)-2-pyridinyl)-1,5-hexa nediol) was examined for its ability to inhibit the "late-phase" bronchopulmonary eosinophilia that occurs 6 to 24 h after inhalation of specific antigen in sensitized guinea pigs. Groups of 6 male guinea pigs, sensitized with ovalbumin, were pretreated with U-75302, 1.0, 10.0, or 30.0 mg/kg, or vehicle 1 h before and 7 h after antigen inhalation. Twenty-four hours after antigen provocation, the lungs were lavaged for the enumeration of inflammatory cell populations. Doses of U-75302 (1.0, 10.0 and 30.0 mg/kg) administered orally produced 12.2%, (p greater than 0.05), 43.2% (p less than 0.05), and 61.1% (p less than 0.05) inhibition, respectively, of the antigen-induced influx of eosinophils into the bronchial lumen. Neutrophil populations were not significantly affected by treatment with U-75302. In a separate study, we compared the histopathological changes that occurred following antigen challenge in U-75302-treated or vehicle-treated guinea pigs. Vehicle-treated, sensitized animals exhibited marked changes in the airway at 8 min, 6 h, and 24 h after antigen challenge. U-75302 treatment produced a significant reduction in eosinophil adherence to peribronchial/peribronchiolar capillaries followed by a dramatic and specific reduction of peribronchial eosinophil infiltration (81% reduction at 6 h and 79% reduction at 24 h). Neutrophil migration appeared unaffected. These data implicate LTB4 as a mediator of antigen-induced bronchopulmonary eosinophilia in the guinea pig.
Richards
I M
IM
Hypersensitivity Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
Griffin
R L
RL
Oostveen
J A
JA
Morris
J
J
Wishka
D G
DG
Dunn
C J
CJ
D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004804:Eosinophils / Q000473:pathology; D005233:Fatty Alcohols / Q000494:pharmacology*; D006018:Glycols / Q000494:pharmacology*; D006168:Guinea Pigs; D007114:Immunization; D007962:Leukocytes / Q000473:pathology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D008168:Lung / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000473:pathology; D010047:Ovalbumin / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000209:etiology / Q000276:immunology / Q000473:pathology*
D000941:Antigens; D005233:Fatty Alcohols; D006018:Glycols; C062137:U 75302; D007975:Leukotriene B4; D010047:Ovalbumin