Reactive Intermediates in Leukocyte Systems

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This project by C. Foote and R. Lehrer of UCLA is within the Chemistry of Life Processes Program, jointly supported by Organic Dynamics of the Chemistry Division and Cell Biology of the Division of Cellular Biosciences. This work deals with the role of white blood cells in the defense against infection. Efforts will be made to learn the details about how oxygen is utilized during this process. The active chlorinating species and other strong oxidants in the antimicrobial action of human polymorphonuclear leukocytes (PMNs), eosinophils and macrophages will be characterized by chemical means. A quantitative trimethoxybenzene assay will be used for the production of hypochlorous acid, and systems will be designed to trap other possible oxidizing species in defined locations in both the interior and exterior of these cells. Reactions of HOCl and other chlorinating agents will be studied to obtain chemical fingerprints for various positive chlorine species "in vitro" and in cells. Although it is likely that HOCl or a similar species is the major oxygen-dependent antimicrobial species of the neutrophil (HOBR in the eosinophil), an unresolved problem is the mechanism by which macrophages (which lack the MPO of PMNs) and MPO-deficient PMNs kill organisms. This mechanism might involve singlet oxygen, other active oxygen species, or something else. Singlet oxygen detection methodology will be further refined, and technology will be developed for the detection of other reactive species to attack this problem. Attempts to detect singlet oxygen quantitatively in eosinophils and further improvements on the halogen assay will be made. Chemical probes for singlet oxygen, halogens, and other species which are covalently bonded to readily-phagocyzed polymer microbeads should provide useful, localizable probes for the white-cell phagocytic vacuole. This should allow an answer to the question of whether all the oxidant is produced within the phagocytic vesicle or whether some escapes to the media.