Superoxide dismutase mimetics inhibit neutrophil-mediated human aortic endothelial cell injury in vitro.
In this study, we evaluated the ability of low molecular weight manganese-based superoxide dismutase mimetics to attenuate neutrophil-mediated oxygen radical damage to human aortic endothelial cells in vitro. Human neutrophils, when exposed to tumor necrosis factor-alpha and the complement compound C5a, induced endothelial damage assessed by the release of 51Cr into the medium. This damage correlated with the amount of superoxide generated by neutrophils. Three superoxide dismutase mimetics, with catalytic rate constants for superoxide dismutation ranging from 4 to 9 x 10(7) M-1 S-1, inhibited neutrophil- or xanthine oxidase-mediated endothelial cell injury in a concentration-dependent manner. A similar manganese-based compound with no detectable superoxide dismutase activity was ineffective in inhibiting injury. Fluorescent studies of the neutrophil respiratory burst showed that the superoxide dismutase mimetics were protective without interfering with the generation of superoxide by activated neutrophils. Catalase, elastase inhibitors, and desferrioxamine mesylate (an iron chelator and hydroxyl radical scavenger) were not protective against cell injury. This investigation demonstrates that neutrophil-mediated human aortic endothelial cell injury in vitro is mediated by the superoxide anion and that low molecular weight manganese-based superoxide dismutase mimetics are effective in abrogating this damage.
Hardy
M M
MM
Department of Health Sciences, Monsanto Company, St. Louis, Missouri 63167.
Flickinger
A G
AG
Riley
D P
DP
Weiss
R H
RH
Ryan
U S
US
D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D015936:Complement C5a / Q000633:toxicity*; D003676:Deferoxamine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000473:pathology*; D005029:Ethylenediamines / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008345:Manganese / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D013482:Superoxide Dismutase / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D014969:Xanthine Oxidase / Q000633:toxicity
D000975:Antioxidants; D005029:Ethylenediamines; D009842:Oligopeptides; D009942:Organometallic Compounds; D014409:Tumor Necrosis Factor-alpha; D008345:Manganese; D015936:Complement C5a; D002374:Catalase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D010196:Pancreatic Elastase; D003676:Deferoxamine; C010718:elastatinal; D013755:Tetradecanoylphorbol Acetate