Effect of a 5-lipoxygenase inhibitor and leukotriene antagonist (PF 5901) on PAF-induced airway responses in neonatally immunized rabbits.
1. Aerosol administration of platelet activating factor (PAF) (80 micrograms ml-1 for 60 min) to neonatally immunized rabbits caused bronchoconstriction which was far in excess of that produced by a comparable aerosol of bovine serum albumin (BSA), the carrier molecule for PAF. Bronchoconstriction of a similar magnitude was elicited by PAF in immunized, sham-immunized and normal rabbits. 2. Aerosol administration of PAF to immunized rabbits induced enhanced airway responsiveness to inhaled histamine in all animals tested, 24 h and 72 h after exposure. In not all cases had airways responsiveness returned to basal levels at 1 week following PAF challenge. In contrast, following exposure of immunized rabbits to BSA, no significant changes in airway responsiveness to histamine were evident at any of the measured time points. 3. A significant increase in the total number of inflammatory cells recovered in bronchoalveolar lavage (BAL) fluid was determined 24 h and 72 h following PAF exposure in immunized rabbits. This was associated with a significant increase in the number of neutrophils and eosinophils. Similar changes were observed following exposure of PAF to normal and sham-immunized rabbits. No change in the total number of inflammatory cells was obtained in BAL after BSA challenge to immunized rabbits; however, neutrophil numbers were significantly increased. 4. PF 5901, a specific inhibitor of the 5-lipoxygenase pathway of arachidonic acid metabolism and a leukotriene D4 antagonist, at a dose of 10 mg (direct intratracheal administration) significantly inhibited the airway resistance (RL) component of the bronchoconstriction induced by PAF in neonatally-immunized rabbits. Doses of 10 mg, 3 mg and 1 mg PF 5901 (direct intratracheal administration) were sufficient to inhibit significantly the PAF-induced increase in airways responsiveness to inhaled histamine in immunized rabbits. PF 5901 however, failed to alter the pulmonary cell infiltration induced by PAF,as assessed by BAL.5. We suggest from the results of the present study that PAF induces consistent and long-lasting increases in airways responsiveness to histamine in immunized rabbits, which is mediated, at least in part, by products of the 5-lipoxygenase metabolic pathway. Furthermore, the inability of PF 5901 to inhibit the influx of inflammatory cells into the airway lumen following PAF challenge may suggest that bronchial hyperresponsiveness and cellular infiltration are not strictly associated events.
Herd
C M
CM
Department of Pharmacology, King's College London.
Donigi-Gale
D
D
Shoupe
T S
TS
Page
C P
CP
D000280:Administration, Inhalation; D000485:Allergens; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects*; D002452:Cell Count; D005260:Female; D006632:Histamine / Q000494:pharmacology; D007114:Immunization; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011817:Rabbits; D013189:SRS-A / Q000037:antagonists & inhibitors*
D000485:Allergens; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D011804:Quinolines; D013189:SRS-A; C049740:alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; D006632:Histamine