The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury

• Published in: The American review of respiratory disease Vol. 137; no. 6; p. 1343
• Main Authors: Farrukh, I S, Michael, J R, Peters, S P, Sciuto, A M, Adkinson, Jr, N F, Freeland, H S, Paky, A, Spannhake, E W, Summer, W R, Gurtner, G H
• Format: Journal Article
• Language: English
• Published: United States 01-06-1988
• Subjects: 5,8,11,14-Eicosatetraynoic Acid - pharmacology; 6-Ketoprostaglandin F1 alpha - biosynthesis; Animals; Blood Pressure - drug effects; Chromones - pharmacology; Free Radicals; Indomethacin - pharmacology; Leukotrienes - metabolism; Lipoxygenase - physiology; Lung - metabolism; Lung - pathology; Lung Diseases - chemically induced; Lung Diseases - enzymology; Male; Organ Size - drug effects; Oxygen - biosynthesis; Peroxides - antagonists & inhibitors; Peroxides - pharmacology; Prostaglandin-Endoperoxide Synthases - physiology; Pulmonary Artery - drug effects; Rabbits; tert-Butylhydroperoxide; Thromboxane B2 - biosynthesis
• ISSN: 0003-0805
• DOI: 10.1164/ajrccm/137.6.1343

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.