FR-110302

Airway hyperresponsiveness is a key feature of asthma, and attenuating airway hyperresponsiveness is an important part of asthma therapy. In the present study we examined the inhibitory effect of a potent 5-lipoxygenase inhibitor, FR110302, on airway hyperresponsiveness induced by ozone exposure in guinea pigs and dogs. Respiratory resistance (Rrs) was measured by a forced oscillation method. Airway responsiveness was determined from the dose-response curve of Rrs to acetylcholine. Guinea pigs were exposed to 2.5 ppm ozone for 1 h. In a control group of guinea pigs, delta log PC100 (the index of the ozone-induced airway hyperresponsiveness) was 0.58 +/- 0.04 (log mg/ml). Treatment with FR110302 (10 or 100 mg/kg p.o.) significantly diminished delta log PC100 (10 mg/kg: 0.22 +/- 0.10; 100 mg/kg; 0.11 +/- 0.06). Dogs were exposed to 3 ppm ozone for 2 h. In a control group of dogs, delta log Dmin (another index of the ozone-induced airway hyperresponsiveness) was 1.24 +/- 0.15 (log unit). Treatment with FR110302 (1 or 3.2 mg/kg p.o.) significantly diminished delta log Dmin (1 mg/kg: 0.60 +/- 0.18; 3.2 mg/kg: 0.27 +/- 0.12). These results suggest that FR110302 may be a useful drug for attenuating airway hyperresponsiveness in asthmatic patients.

To study the role of chemical mediators in airway hyperresponsiveness and simultaneous eosinophilia, we examined effects of a potent 5-lipoxygenase inhibitor FR110302 and those of prednisolone, indomethacin, platelet-activating factor (PAF) antagonist (RP-59227) and leukotriene C4 (LTC4) antagonist (ONO-1078) on airway hyperresponsiveness and lung eosinophilia induced by Sephadex particles. Sephadex G200 particles (2.5 mg/kg) were injected intravenously to rats and 3 days later the airway hyperresponsiveness to acetylcholine (ACh) and the eosinophilia in the bronchoalveolar lavage (BAL) fluids were observed. FR110302 (10 mg/kg b.i.d.p.o.) significantly suppressed both of these indicators of asthma. The amounts of immunoreactive LTB4,C4 (i-LTB4, C4) in the BAL fluid were measured by radioimmunoassay. The amounts of i-LTB4,C4 in the FR110302-treated rats were significantly less compared with that in the Sephadex-injected controls. Prednisolone completely inhibited the airway hyperresponsiveness. PAF antagonist and LTC4 antagonist partially inhibited the airway hyperresponsiveness, and indomethacin had no effect. The results indicate that 5-lipoxygenase products play important roles in the Sephadex-induced airway hyperresponsiveness and lung eosinophilia in rats.