EFFECT OF A 5-LIPOXYGENASE INHIBITOR AND LEUKOTRIENE ANTAGONIST (PF-5901) ON ANTIGEN-INDUCED AIRWAY RESPONSES IN NEONATALLY IMMUNIZED RABBITS

1 The effect of a single intratracheal dose (10 mg) of PF 5901 (2-3(1 -hydroxyhexyl) phenoxymethyl quinoline hydrochloride, a specific inhi bitor of the 5-lipoxygenase pathway of arachidonic acid metabolism and a leukotriene D-4 antagonist) on airway changes induced in response t o Alternaria tenuis aerosol challenge was assessed in adult rabbits ne onatally immunized. Leukotriene generation was determined in vivo by m easuring leukotriene B-4 (LTB(4) levels in bronchoalveolar lavage (BAL ) fluid and ex vivo by measuring calcium ionophore-stimulated producti on of LTB(4) in whole blood. 2 While PF 5901 (10 mg) had no significan t effect on the acute bronchoconstriction induced by antigen, this dos e was sufficient to inhibit significantly the increase in airway respo nsiveness to inhaled histamine 24 h following antigen challenge (P<0.0 5). 3 Total leucocyte infiltration into the airways induced by antigen , as assessed by bronchoalveolar lavage, was significantly inhibited b y pretreatment with PF 5901 (10 mg). However, the pulmonary infiltrati on of neutrophils and eosinophils induced by antigen was unaltered by prior treatment with PF 5901 (10 mg). 4 PF 5901 (10 mg) had no effect on ex vivo LTB(4) synthesis in whole blood. However, the antigen-induc ed increase in LTB(4) levels in BAL 24 h following challenge was signi ficantly inhibited (P<0.05). 5 We suggest from the results of the pres ent study that the antigen-induced airway hyperresponsiveness to inhal ed histamine in immunized rabbits is mediated, at least in part, by pr oducts of the 5-lipoxygenase metabolic pathway, and is not dependent o n the extent of eosinophil or neutrophil influx into the airway lumen.