Effects of TMK-688 a potent 5-lipoxygenase inhibitor, on dual-phase asthmatic response in conscious guinea pigs sensitized with ovalbumin

ABSTRACTWe evaluated the anti-asthmatic effects and mechanism of action of TMK-688, a potent 5-lipoxygenase inhibitor, on the dual-phase asthmatic response and on airway inflammation in conscious guinea pigs sensitized with ovalbumin (OA). TMK-688 inhibited both the immediate and the late asthmatic response (LAR) after administration of a single oral dose of 3.2 or 10mg/kg 2h before OA challenge. Pretreatment with TMK-688 also inhibited airway hyperresponsiveness to acetylcholine. The increase in eosinophils in bronchoalveolar lavage fluid and the production of reactive oxygen, an index of cell activation during LAR, was also suppressed by TMK-688. These findings suggest the following inhibitory mechanism of LAR by TMK-688: (i) a reduction of eosinophil accumulation in airways; (ii) the inhibition of the immediate asthmatic response; (iii) the inhibition of airway hyperresponsiveness; and (iv) the suppression of the generation of reactive oxygen from bronchoalveolar lavage cells