LIPID MEDIATORS CONTRIBUTE TO OXYGEN-RADICAL-INDUCED AIRWAY RESPONSES IN SHEEP

The purpose of this study was to determine if the bronchoconstriction and airway hyperresponsiveness (AHR) resulting from aerosolized xanthine (x; 0.1%)-xanthine oxidase (xo; 4.1 U) and the subsequent production of oxygen radicals is mediated by the secondary generation of lipid mediators. In seven conscious sheep, specific lung resistance (SRL) was measured before and after x-xo challenge; approximately 30 min later when SRL had returned to baseline, airway responsiveness to carbachol was determined from dose-response curves by calculating the cumulative provocating dose of carbachol in breath units (BU, defined as one breath of a 1% wt/vol carbachol solution) that Increased SRL 400% over baseline (PD400). Inhaled x-xo caused in immediate increase in SRL of 162 +/- 36% (mean +/- SE; p < 0.05) over baseline and decreased PD400 from a baseline value of 32.5 +/- 5.0 to 16.6 +/- 1.7 BU (p < 0.05). Pretreatment with the H2O2 scavenger, catalase (CAT,; 38 mg aerosol), methylprednisolone succinate (MS; 1 mg/kg given intravenously), the cyclooxygenase inhibitor, indomethacin (IND; 2 mg/kg given intravenously), and the PAF antagonist, WEB-2086 (3 mg/kg given intravenously) all attenuated the x-xo-induced increase in SRL (p < 0.05); the leukotriene D, antagonist, MK-571 (5 mg by aerosol) had no effect. All agents inhibited the x-xo-induced decrease in PD400: mean BUs were 27 after CAT, 32 after WEB-2086, 34 after IND, 31 after MS, and 25 after MK-571 (all p < 0.05 versus x-xo alone). In a cell-free system in vitro, x-xo produced 774 +/- 41 ng OH./ml (n = 9) and CAT (50-mu-g/ml) inhibited this reaction by 74 +/- 11% (n = 7, p < 0.05); all other drugs were ineffective, indicating that they did not have nonspecific radical scavenging action. In subsequent experiments, CAT pretreatment had no effect on PAF-Induced bronchoconstriction or AHR, suggesting that radical-induced generation of lipid mediators occurred first. These results suggest that in sheep, the secondary generation of arachidonic acid metabolites contributes to x-xo-induced bronchoconstriction and AHR.