The role of 5-lipoxygenase products in preclinical models of asthma.
BACKGROUND
The action of 5-lipoxygenase on arachidonic acid generates potent inflammatory mediators that may contribute to the pathophysiology of asthma.


METHODS
Using the potent and selective 5-lipoxygenase inhibitor BI-L-239, we have examined the role of 5-lipoxygenase products in three animal models of asthma.


RESULTS
In vitro BI-L-239 inhibited 5-lipoxygenase product generation from human lung mast cells, alveolar macrophages, and peripheral blood leukocytes with a concentration that would provide 50% inhibition values of 28 to 340 nmol/L. A 36-fold selectivity for immunoreactive leukotriene C4 versus immunoreactive prostaglandin D2 inhibition was demonstrated in mast cells. In anesthetized cynomolgus monkeys, inhaled BI-L-239 provided dose-dependent inhibition of the inhaled Ascaris-induced immunoreactive leukotriene C4 release (maximum, 73%; bronchoalveolar lavage [BAL], 20 minutes), late-phase bronchoconstriction (maximum, 41%; +6 to 8 hours), and neutrophil infiltration (maximum, 63%; BAL, +8 hours). In conscious sheep, inhaled BI-L-239 provided dose-dependent inhibition of the inhaled Ascaris-induced late-phase bronchoconstriction (maximum, 66%; +6 to 8 hours) and increase in airway responsiveness (maximum, 82%; carbachol, +24 hours). The acute bronchoconstriction was shortened, and neutrophil infiltration diminished (maximum, 61%; BAL, +8 hours) in this model. Finally in conscious actively sensitized guinea pigs pretreated with pyrilamine and indomethacin, inhaled BI-L-239 attenuated acute bronchoconstriction (maximum, 80%; +5 to 15 minutes), leukocyte infiltration (58%; BAL, +3 days) and increase in airway responsiveness (100%; methacholine, +3 days) induced by three alternate-day ovalbumin inhalations.


CONCLUSIONS
In conclusion, results in these three animal models indicate that 5-lipoxygenase products may be major contributors to the bronchoconstriction (especially late phase), leukocyte infiltration, and airway hyperresponsiveness that characterize asthma.
Wegner
C D
CD
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877.
Gundel
R H
RH
Abraham
W M
WM
Schulman
E S
ES
Kontny
M J
MJ
Lazer
E S
ES
Homon
C A
CA
Graham
A G
AG
Torcellini
C A
CA
Clarke
C C
CC
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology*; D001249:Asthma / Q000503:physiopathology*; D016084:Bronchoconstriction; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D010636:Phenols / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000378:metabolism; D013189:SRS-A / Q000378:metabolism; D012756:Sheep
D016859:Lipoxygenase Inhibitors; D010636:Phenols; D013189:SRS-A; C067524:enofelast; D001094:Arachidonate 5-Lipoxygenase; D015230:Prostaglandin D2