The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury.
Infusion of the oxidant lipid peroxide tert-butyl hydroperoxide (t-bu-OOH) causes pulmonary vasoconstriction and increases vascular permeability in isolated perfused rabbit lungs. We have previously shown that t-bu-OOH stimulates arachidonic acid metabolism, increasing the synthesis of the cyclooxygenase products. The current experiments were designed to determine the role that cyclooxygenase- and lipoxygenase-derived mediators play in the lung injury caused by t-bu-OOH. In the present experiments, we found that t-bu-OOH not only increased the synthesis of the cyclooxygenase-derived products thromboxane and prostacyclin but also increased the synthesis of the lipoxygenase-derived products leukotrienes B4, C4, D4, and E4. To determine the role that these arachidonic acid metabolites play in the increase in pressure and vascular permeability caused by t-bu-OOH, we studied the effect that inhibitors of arachidonic acid metabolism or a leukotriene receptor blocker had on the pulmonary edema. We compared an uninjured control group with 4 groups of lungs given t-bu-OOH: a t-bu-OOH control group; a group pretreated with the cyclooxygenase inhibitor indomethacin (14 microM); a group pretreated with an analogue of arachidonic acid, 5-, 8-, 11-, 14-eicosatetraynoic acid (ETYA) (100 microM), that inhibits both the cyclooxygenase and lipoxygenase pathways; and a group pretreated with the leukotriene receptor antagonist FPL 55712 (38 microM). To produce lung injury, t-bu-OOH (300 microM) was infused throughout the first minute of 4 successive 10-min periods.(ABSTRACT TRUNCATED AT 250 WORDS)
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D005609:Free Radicals; D007213:Indomethacin / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism; D008084:Lipoxygenase / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010100:Oxygen / Q000096:biosynthesis; D010545:Peroxides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects; D011817:Rabbits; D013929:Thromboxane B2 / Q000096:biosynthesis; D020122:tert-Butylhydroperoxide
D002867:Chromones; D005609:Free Radicals; D015289:Leukotrienes; D010545:Peroxides; D015117:5,8,11,14-Eicosatetraynoic Acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C006312:FPL 55712; D020122:tert-Butylhydroperoxide; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D010100:Oxygen; D007213:Indomethacin