EFFECTS OF THE PLATELET-ACTIVATING-FACTOR ANTAGONISTS BN-52021 AND BN-50730 ON ANTIGEN-INDUCED BRONCHIAL HYPERRESPONSIVENESS AND EOSINOPHILINFILTRATION IN LUNG FROM SENSITIZED GUINEA-PIGS

The involvement of platelet activating factor (PAF) in antigen-induced bronchial hyperresponsiveness was investigated by the use of the PAF antagonists BN 52021 and BN 50730, in a guinea-pig model where sensiti zation and challenge were performed by aerosol. Male Hartley guinea-pi gs were sensitized by two aerosol exposures at 48 hr intervals to a 0. 9% NaCl solution (saline) containing 2 mg/ml ovalbumin for 30 min. Fif teen to 20 days later, guinea-pigs were challenged by exposure to five successive aerosols of increasing concentrations of ovalbumin (OA) or respectively, 10 mu g/ml, 100 mu g/ml, 1 mg/ml, 5 mg/ml and 10 mg/ml for 15 min each, or saline alone. Three to four hr and 18-24 hr after the aerosol challenge the guinea-pigs were prepared for recording of b ronchopulmonary response and aerosol administrations were then generat ed with an ultrasonic nebulizer. The bronchopulmonary responses induce d by successive 1-min aerosol bursts of acetylcholine (ACh) was assess ed. As compared with saline-challenged guinea-pigs, an enhanced bronch opulmonary response to aerosol administration of cumulative doses of A Ch was observed, 3-4 hr and 18-24 hr post-ovalbumin challenge. When th e sensitized guinea-pigs were pretreated 1 hr before ovalbumin exposur e with BN 52021 or BN 50730 (25 mg/kg, per os), a significant inhibiti on of the increase in the bronchopulmonary response to ACh was observe d, both at 3-4 hr and 18-24 hr. Furthermore, when guinea-pigs were tre ated 3-4 hr after the ovalbumin exposure with BN 52021 or BN 50730, a significant inhibition of the hyperresponsiveness to ACh was recorded at 18-24 hr. A marked accumulation of eosinophils in the peribronchial regions was observed on histological preparations of lung specimens c ollected 4 hr or 24 hr after ovalbumin exposure. Pretreatment of the g uinea-pigs by BN 50730 or BN 52021 did not modify the eosinophil accum ulation in the peribronchial area. No significant difference in the nu mber of eosinophils collected in the bronchoalveolar lavage fluid is o bserved, 24 hr post-ovalbumin challenge, under the pretreatment with B N 52021 or BN 50730. Pretreatment of guinea-pigs by BN 50730 or BN 520 21 significantly reduced he PAF-induced (100 mu g/ml) increase in eosi nophil number in the peribronchial area. By contrast, they did not inh ibit the eosinophilia induced by aerosol administration of LTB(4) (5 m u g/ml). These results suggest that the bronchial hyperresponsiveness observed in this study is associated with eosinophil accumulation in t he lung. The potent inhibition of the bronchial hyperresponsiveness by the two unrelated antagonists of PAF suggests that the lipid mediator is involved in its triggering and duration, but not in the eosinophil infiltration.