Eosinophils play an essential role in vivo, destroying pathogenic microorganisms, parasites and tumor cells. To perform these functions they have evolved enzymatic mechanisms to generate an arsenal of reactive oxidant species; however, their potent oxidants also have great potential to harm healthy tissue. Oxidative products of eosinophil activation are implicated in the genesis of tissue injury in asthma. Eosinophil peroxidase (EPO), an abundant heme protein secreted during eosinophil activation, amplifies the oxidizing potential of hydrogen peroxide to generate potent cytotoxic oxidants. Reactive oxidant species generated by EPO in model systems reproduce the pathophysiologic features of asthma. Although substantial evidence implicates EPO-dependent oxidative damage in the pathogenesis of asthma, direct demonstration of the oxidation pathways which are operational in vivo has yet to be established. Two pathways have been identified for EPO-dependent oxidative damage of cellular proteins and lipids which might contribute to the origins of cellular injury in the inflammatory response in asthma: bromination and nitration. EPO is the only known human enzyme which selectively generates reactive brominating species under physiologic concentrations of halides; identification of brominated products in vivo can thus serve as """"""""molecular fingerprints"""""""" identifying sites of EPO-catalyzed oxidative tissue damage. Reactive nitrogen species have been implicated in the genesis of cellular injury in a host of inflammatory disorders, yet neither their production by eosinophils nor their role in oxidative damage during asthma are established. The overall goals of this proposal are to test the hypothesis that eosinophil peroxidase catalyzes oxidative tissue damage in vivo and contributes to the onset of cellular injury in asthma.
The specific aims are: 1) to determine the role of eosinophil peroxidase in oxidative damage of proteins in individuals with asthma; 2) to investigate the biochemical pathways by which eosinophils generate reactive nitrogen species; and 3) to characterize a family of brominated oxysterols synthesized by eosinophil peroxidase and to examine their cytotoxic properties.
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