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 pathophysiol ogy of asthma. Methods: Using the potent and selective 5-lipoxygenase inhibitor BI-L-239, we have examined the role of 5-lipoxygenase produc ts in three animal models of asthma. Results: In vitro BI-L-239 inhibi ted 5-lipoxygenase product generation from human lung mast cells, alve olar macrophages, and peripheral blood leukocytes with a concentration that would provide 50% inhibition values of 28 to 340 nmol/L. A 36-fo ld selectivity for immunoreactive leukotriene C4 versus immunoreactive prostaglandin D2 inhibition was demonstrated in mast cells. In anesth etized cynomolgus monkeys, inhaled BI-L-239 provided dose-dependent in hibition 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 neutroph il infiltration (maximum, 63%; BAL, +8 hours). In conscious sheep, inh aled BI-L-239 provided dose-dependent inhibition of the inhaled Ascari s-induced late-phase bronchoconstriction (maximum, 66%; +6 to 8 hours) and increase in airway responsiveness (maximum, 82%; carbachol, +24 h ours). The acute bronchoconstriction was shortened, and neutrophil inf iltration diminished (maximum, 61%; BAL, +8 hours) in this model. Fina lly in conscious actively sensitized guinea pigs pretreated with pyril amine and indomethacin, inhaled BI-L-239 attenuated acute bronchoconst riction (maximum, 80%; +5 to 15 minutes), leukocyte infiltration (58%; BAL, +3 days) and increase in airway responsiveness (100%; methacholi ne, +3 days) induced by three alternate-day ovalbumin inhalations. Con clusions: In conclusion, results in these three animal models indicate that 5-lipoxygenase products may be major contributors to the broncho constriction (especially late phase), leukocyte infiltration, and airw ay hyperresponsiveness that characterize asthma.