Polymorphonuclear leukocytes (PMN) and monocytes reduce oxygen during phagocytosis and elaborate a battery of oxidants (O2, H2O2, and 1O2) capable of inflicting damage to microbes and to surrounding tissues. Phagocytic cells may sustain autooxidative damage resulting in selective alterations of membrane-related and microtubule-related functions; membrane related include adherence, chemotaxis, recognition of opsonized particles and their ingestion; whereas, microtubule related functions include directed cell movement, distribution of lectin receptors in the cell surface, degranulation, and secretion of granular contents of the cell. This project will focus on the biochemical, cytoskeletal, and functional consequences of excessives and deficiencies of oxidation and oxygenation reactions in human and animal PMN and monocytes. The major objectives of this proposal are to locate the site of preferred substrate of the oxidase(s) responsible for the production of oxidants in mature and developing phagocytes, to define the natural antioxidants and their biochemical mechanisms which protect cytoskeletal components of the cell, to detail the alterations of membrane adherence, fluidity, receptor activity, microfilamatous gelation and contraction reactions in the phagocyte lacking Vitamin E, to determine the influence of prostaglandins and prostacyclins, especially PGE2 and PGI2 on membrane and cytoplasmic-associated phagocytic function, to investigate the pathologic consequences of iron overload, dietary excessives of polyunsaturates phagocytic function and to more precisely define the cellular basis for our observed beneficial effects of the oxidant drugs, ascorbic acid and dapsone, in the Chediak-Higashi syndrome and chronic granulomatous disease respectively.
