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 less than 0.05) over baseline and decreased PD400 from a baseline value of 32.5 +/- 5.0 to 16.6 +/- 1.7 BU (p less than 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 less than 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 less than 0.05 versus x-xo alone).(ABSTRACT TRUNCATED AT 250 WORDS)
Lansing
M W
MW
Division of Pulmonary Disease, University of Miami, Mount Sinai Medical Center, Miami Beach, Florida.
Mansour
E
E
Ahmed
A
A
Cortes
A
A
Garcia
L
L
Lauredo
I T
IT
Wanner
A
A
Abraham
W M
WM
D000818:Animals; D016718:Arachidonic Acid / Q000502:physiology; D001249:Asthma / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000209:etiology* / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D015777:Eicosanoids / Q000502:physiology*; D005260:Female; D016166:Free Radical Scavengers; D005609:Free Radicals / Q000009:adverse effects; D010100:Oxygen / Q000009:adverse effects*; D010972:Platelet Activating Factor / Q000502:physiology; D011292:Premedication; D012756:Sheep
D015777:Eicosanoids; D016166:Free Radical Scavengers; D005609:Free Radicals; D010972:Platelet Activating Factor; D016718:Arachidonic Acid; D010100:Oxygen