Superoxide dismutase potentiates platelet-activating factor-induced injury in perfused lung.
Platelet-activating factor (PAF) causes pulmonary hypertension and lung edema in animals and isolated perfused lungs by poorly understood mechanisms. Because oxidative mechanisms have been implicated in PAF-mediated cellular injury, we tested the hypothesis that superoxide anion (O2-.) contributes to PAF-induced lung injury by determining whether superoxide dismutase (SOD) could prevent the lung injury. Isolated rabbit lungs were perfused with PAF (100 nM) at a dose that caused transient hypertension and mild edema. Lungs pretreated with Cu,Zn SOD (100 U/ml) for 10 min developed persistent pulmonary hypertension and more lung edema formation in response to PAF. Enhanced responses to PAF also were observed in lungs perfused with 200 U/ml Cu,Zn SOD, but not with 10 or 40 U/ml Cu,Zn SOD. The higher doses of SOD also decreased thromboxane B2 levels in the perfusate. Potentiation of the PAF effect by Cu,Zn SOD was eliminated if the enzyme was inactivated or if the lung was treated with an anion channel blocker. The augmented PAF response in the presence of SOD was not altered by catalase (200 U/ml) or by nitric oxide synthase inhibitor. The data suggest that excessive Cu,Zn SOD enzyme activity potentiates PAF-induced injury in perfused rabbit lung presumably by overscavenging extracellular O2.- generated from intercellular sources. The augmented responses to PAF are not directly attributable to increased hydrogen peroxide, nitric oxide-related products, or thromboxane A2 production. These results suggest the new hypothesis that a balance between O2-. production and its metabolism determines vascular and endothelial responses to PAF.
Huang
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YC
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Nozik
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ES
Piantadosi
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CA
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D002374:Catalase / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D019001:Nitric Oxide Synthase; D010477:Perfusion; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011817:Rabbits; D013482:Superoxide Dismutase / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000096:biosynthesis
D010972:Platelet Activating Factor; D013928:Thromboxane A2; D004050:Ditiocarb; D011464:Epoprostenol; D002374:Catalase; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D000594:Amino Acid Oxidoreductases; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid