Abstract
U-74006F, a non-glucocorticoid 21-aminosteroid, has been developed as an inhibitor of iron-dependent lipid peroxidation. This class of compounds has been shown to prevent antigen-induced eosinophil accumulation in the lungs. In this study, Ascaris-sensitive, "dual-respondent" sheep (showing both immediate (IAR) and late (LAR) asthmatic response) (n = 6) were used to assess the effect of U-74006F on antigen-induced bronchoconstriction and airway inflammation and reactivity 8 h after antigen challenge. Antigen provocation induced dual-phase bronchoconstriction, bronchoalveolar eosinophilia and airway hyperreactivity (AHR) to methacholine. Throughout the experiment, intravenous administration of the drug significantly reduced the IAR and inhibited the LAR along with the inhibition of eosinophil influx, but did not inhibit the increase in airway reactivity observed 8 h after antigen challenge. Post-antigen challenge treatment with U-74006 from 3 h after antigen challenge also significantly reduced the LAR and bronchoalveolar eosinophilia, although the degree of inhibitory effect was milder. The development of the LAR appeared to be dependent on eosinophil recruitment into the lungs. These findings suggest that lipid peroxidation is involved in antigen-induced bronchoconstriction and eosinophil recruitment into the lungs, and that the inhibitor U-74006F may be an effective drug for the treatment of bronchoconstriction and airway inflammation characterized by eosinophil infiltration in asthmatics.
