SUPEROXIDE-DISMUTASE MIMETICS INHIBIT NEUTROPHIL-MEDIATED HUMAN AORTIC ENDOTHELIAL-CELL INJURY IN-VITRO

In this study, we evaluated the ability of low molecular weight mangan ese-based superoxide dismutase mimetics to attenuate neutrophil mediat ed oxygen radical damage to human aortic endothelial cells in vitro. H uman neutrophils, when exposed to tumor necrosis factor-alpha and the complement component C5a, induced endothelial damage assessed by the r elease of Cr-51 into the medium. This damage correlated with the amoun t of superoxide generated by neutrophils. Three superoxide dismutase m imetics, with catalytic rate constants for superoxide dismutation rang ing 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 superox ide dismutase activity was ineffective in inhibiting injury. Fluoresce nt studies of the neutrophil respiratory burst showed that the superox ide dismutase mimetics were protective without interfering with the ge neration of superoxide by activated neutrophils. Catalase, elastase in hibitors, and desferrioxamine mesylate (an iron chelator and hydroxyl radical scavenger) were not protective against cell injury. This inves tigation demonstrates that neutrophil-mediated human aortic endothelia l cell injury in vitro is mediated by the superoxide anion and that lo w molecular weight manganese-based superoxide dismutase mimetics are e ffective in abrogating this damage.