ROLE OF LIPOXYGENASE METABOLITES IN PLATELET-ACTIVATING FACTOR-INDUCED AND ANTIGEN-INDUCED BRONCHIAL HYPERRESPONSIVENESS AND EOSINOPHIL INFILTRATION

The effect of a novel leukotriene B-4 receptor antagonist [8-(1-hydrox y-2-phenyl)ethyl]dibenzofuran-2-yl]-5- hydroxypentanoyl]pyrrolidine (P F 10042) has been evaluated in comparison with 2-[3-(1-hydroxyhexyl)ph enoxy methyl]quinoline hydrochloride (PF 5901), a specific inhibitor o f the 5-lipoxygenase pathway of arachidonic acid metabolism, against p latelet activating factor (PAF) and allergen induced bronchial hyperre sponsiveness and pulmonary eosinophil infiltration in the guinea pig. PF 10042 significantly displaced radiolabelled [H-3]leukotriene B-4 fr om binding sites on human neutrophils with an EC(50) of 3 mu M. PF 100 42 (100 mg/kg, i.p,) significantly inhibited PAF and allergen induced bronchial hyperresponsiveness without reducing the concomitant eosinop hil infiltration, whereas PF 5901 (100 mg/kg, p.o.) significantly inhi bited both PAF and allergen induced bronchial hyperresponsiveness and eosinophil infiltration. We suggest from these results that PAF and al lergen induced bronchial hyperresponsiveness may be secondary to the r elease of leukotriene B-4, but this lipoxygenase metabolite does not c ontribute significantly to the observed eosinophil infiltration.