TY - JOUR
T1 - Lipid mediators contribute to oxygen-radical-induced airway responses in sheep
AU - Lansing, M. W.
AU - Mansour, E.
AU - Ahmed, A.
AU - Cortes, A.
AU - Garcia, L.
AU - Lauredo, I. T.
AU - Wanner, A.
AU - Abraham, W. M.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 1991
Y1 - 1991
N2 - 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.
AB - 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.
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U2 - 10.1164/ajrccm/144.6.1291
DO - 10.1164/ajrccm/144.6.1291
M3 - Article
C2 - 1741541
AN - SCOPUS:0026335863
VL - 144
SP - 1291
EP - 1296
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 6
ER -