Leukotrienes mediate antigen-induced airway hyper-reactivity in guinea pigs.
The involvement of leukotrienes (LTs) in antigen-induced airway hyper-reactivity (AHR) was characterized pharmacologically by using several 5-lipoxygenase (5-LO) inhibitors and LTD4 antagonists in guinea pigs. AHR was evidenced by consistent and significant increases in sensitivity to bronchoconstriction induced by i.v. methacholine in anesthetized and ventilated animals 24 hr after a single ovalbumin aerosol challenge, but maximum methacholine-induced bronchoconstriction did not increase. Animals were pretreated with maximum doses of WY-50,295 tromethamine (WY-50,295), LY-171,883, MK-886 or zileuton, based upon inhibition of antigen-induced LT-dependent bronchoconstriction. WY-50,295, having a long duration of action, was the only compound that prevented AHR when given once before antigen challenge. However, LY-171,883 and MK-886 prevented AHR when a second dose was given 4 hr after challenge. Zileuton, having a short duration of action, failed to prevent AHR when given before and after challenge. The prevention of AHR did not result from functional antagonism (bronchodilation) by any compound. In bronchoalveolar lavage studies, neither WY-50,295 nor MK-886 inhibited the influx of eosinophils into the airways 24 hr after antigen challenge. The results provide pharmacological evidence that LTs play an important role in the pathogenesis of antigen-induced AHR in guinea pigs. Furthermore, the effectiveness of 5-LO inhibitors and LTD4 antagonists in this model depends upon a long duration of drug action and appears to result from inhibition of a direct airway effect of LTs rather than inhibition of eosinophil influx into the airways.(ABSTRACT TRUNCATED AT 250 WORDS)
Howell
R E
RE
Inflammation/Bone Metabolism Divisionm, Wyeth-Ayerst Research, Princeton, New Jersey.
Sickels
B D
BD
Woeppel
S L
SL
Jenkins
L P
LP
Rubin
E B
EB
Weichman
B M
BM
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000941:Antigens / Q000276:immunology*; D016084:Bronchoconstriction / Q000187:drug effects* / Q000276:immunology; D004802:Eosinophilia / Q000188:drug therapy; D006168:Guinea Pigs; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors; D015289:Leukotrienes / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009280:Naphthaleneacetic Acids / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D013777:Tetrazoles / Q000494:pharmacology; D002722:Chlorobenzenes
D000098:Acetophenones; D000941:Antigens; D006918:Hydroxyurea; D007211:Indoles; D017998:Leukotriene D4; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D009280:Naphthaleneacetic Acids; D011804:Quinolines; D013777:Tetrazoles; C060893:MK-886; D002722:Chlorobenzenes; C067525:S(alpha)-methyl-6-(2-quinolinylmethoxy)-2-naphthaleneacetic acid; C044660:LY 171883; C063449:zileuton