Lipid mediators contribute to oxygen-radical-induced airway responses in sheep

M. W. Lansing, E. Mansour, A. Ahmed, A. Cortes, L. Garcia, I. T. Lauredo, A. Wanner, William W Abraham

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Abstract

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; ~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 D4 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 μg/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.

Original languageEnglish (US)
Pages (from-to)1291-1296
Number of pages6
JournalAmerican Review of Respiratory Disease
Volume144
Issue number6
DOIs
StatePublished - Jan 1 1991

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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    Lansing, M. W., Mansour, E., Ahmed, A., Cortes, A., Garcia, L., Lauredo, I. T., Wanner, A., & Abraham, W. W. (1991). Lipid mediators contribute to oxygen-radical-induced airway responses in sheep. American Review of Respiratory Disease, 144(6), 1291-1296. https://doi.org/10.1164/ajrccm/144.6.1291