Human granulocytes play a pivotal role in mediating tissue damage in a variety of inflammatory disease states. In order to gain further insight into the pathogenesis of tissue injury during inflammation, our attention will focus on the ability of two populations of phagocytes, neutrophils and eosinophils, to generate oxygen metabolites by peroxidase-dependent processes and to use these oxidants to mediate pro-inflammatory effects. Specific emphasis will be placed on assessing the function of the bromide oxidation product, hypobromous acid, in the human eosinophil and contrasting its role to that of hypochlorous acid in the neutrophil. In addition, myeloperoxidase-deficient neutrophils will be employed to probe potential roles for oxygen-derived, peroxidase-independent metabolities as inflammatory mediators. The significance of these in vitro events will then be extended to a physiologic setting by examining the ability of neutrophils and eosinophils to generate and use halogenated oxidants in plasma- supplemented model systems. Finally, this information will be used to design monitoring systems able to detect and quantitate the predicted generation of halogenated oxidants at inflamed sites in vivo. Taken together, these studies will provide new insights into the role of granulocyte-derived oxidants in the pathogenesis of inflammation at the cellular and molecular level both in vitro and in vivo.
