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 inhibitor of the 5-lipoxygenase pathway of arachidonic acid metabolism and a leukotriene D4 antagonist) on airway changes induced in response to Alternaria tenuis aerosol challenge was assessed in adult rabbits neonatally immunized. Leukotriene generation was determined in vivo by measuring leukotriene B4 (LTB4) levels in bronchoalveolar lavage (BAL) fluid and ex vivo by measuring calcium ionophore-stimulated production of LTB4 in whole blood. 2. While PF 5901 (10 mg) had no significant effect on the acute bronchoconstriction induced by antigen, this dose was sufficient to inhibit significantly the increase in airway responsiveness to inhaled histamine 24 h following antigen challenge (P < 0.05). 3. Total leucocyte infiltration into the airways induced by antigen, as assessed by bronchoalveolar lavage, was significantly inhibited by pretreatment with PF 5901 (10 mg). However, the pulmonary infiltration 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 LTB4 synthesis in whole blood. However, the antigen-induced increase in LTB4 levels in BAL 24 h following challenge was significantly inhibited (P < 0.05). 5. We suggest from the results of the present study that the antigen-induced airway hyperresponsiveness to inhaled histamine in immunized rabbits is mediated, at least in part, by products of the 5-lipoxygenase metabolic pathway, and is not dependent on the extent of eosinophil or neutrophil influx into the airway lumen.
Herd
C M
CM
Department of Pharmacology, Kings College London.
Donigi-Gale
D
D
Shoupe
T S
TS
Burroughs
D A
DA
Yeadon
M
M
Page
C P
CP
D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000528:Alternaria / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects; D005260:Female; D006632:Histamine / Q000008:administration & dosage / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000166:cytology; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D011804:Quinolines / Q000494:pharmacology*; D011817:Rabbits; D012129:Respiratory Function Tests; D012130:Respiratory Hypersensitivity / Q000503:physiopathology*
D016859:Lipoxygenase Inhibitors; D011804:Quinolines; C049740:alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; D007975:Leukotriene B4; D017998:Leukotriene D4; D006632:Histamine