Superoxide dismutase-overexpressing mice are resistant to ozone-induced tissue injury and increases in nitric oxide and tumor necrosis factor-alpha.
Reactive oxygen intermediates have been implicated in lung injury induced by inhaled irritants. The present studies used mice overexpressing Cu/Zn-superoxide dismutase (SOD+/+) to analyze their role in ozone-induced lung inflammation and cytotoxicity. Treatment of wild-type mice with ozone (0.8 ppm, 3 h) resulted in increased bronchoalveolar lavage fluid protein, which was maximal after 24-48 h. Significant increases in lung macrophages and 4-hydroxyalkenals were also observed. In contrast, bronchoalveolar lavage fluid protein and macrophage content and 4-hydroxyalkenals were at control levels in ozone-treated SOD+/+ mice. There was also no evidence of peroxynitrite-mediated lung damage, demonstrating that SOD+/+ mice are resistant to ozone toxicity. Whereas alveolar macrophages from wild-type mice produced increased amounts of nitric oxide and expressed more inducible nitric oxide synthase, phospholipase A(2), and tumor necrosis factor-alpha after ozone inhalation, this was not evident in cells from SOD+/+ mice. Ozone-induced decreases in interleukin-10 were also not observed. In wild-type mice, ozone inhalation resulted in activation of nuclear factor-kappaB, which regulates proinflammatory gene activity. This response was significantly reduced in SOD+/+ mice. These data demonstrate that antioxidant enzymes play a critical role in ozone-induced tissue injury and in inflammatory mediator production.
Fakhrzadeh
Ladan
L
Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ, USA.
Laskin
Jeffrey D
JD
Gardner
Carol R
CR
Laskin
Debra L
DL
D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002470:Cell Survival; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004351:Drug Resistance; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005978:Glutathione / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008168:Lung / Q000201:enzymology; D055370:Lung Injury; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010126:Ozone / Q000008:administration & dosage / Q000633:toxicity*; D030421:Peroxynitrous Acid / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D011014:Pneumonia / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D008315:Malondialdehyde; D010126:Ozone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D013482:Superoxide Dismutase; D010741:Phospholipases A; D005978:Glutathione