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Saturday 20, November, 2004 09:30 - 12:30, 3 hours, International Conference Hall Plenary Session 4 Medical Aspects: Surveillance and Treatment of Asbestos-related Diseases 4-A: Asbestos and Non-asbestos Agents in Mesothelioma Pathogenesis and Immunology Chairs: Yasunosuke Suzuki and Iguchi Hiroshi Tamako Nishiike, Yasumitsu Nishimura, Yasuhiko Wada, Hiroshi Iguchi Department of Hygiene, Hyogo College of Medicine, Japan ABSTRACT: Alveolar macrophages (AMs) phagocytose asbestos and/or man-made mineral fibers (MMMFs) inhaled into the alveolar space, and are stimulated to express inducible nitric oxide (NO) synthase (iNOS) and continuously generate a large amount of NO and other reactive nitrogen species (RNS). Moreover, AMs stimulated by pathogenic particles generate a large amount of reactive oxygen species (ROS) and free radicals. It is widely accepted that ROS and RNS exert oxidative stress on cells and tissues, and cause inflammation and other pathological changes. NO can non-enzymatically react with the free sulfhydryl groups (-SH) of reduced glutathione (GSH) and various proteins to form S-nitrosoglutathione (GS-NO) and S-nitrosothiols (RS-NO), respectively. RS-NO, including GS-NO potentially affects the function of enzymes and other proteins and causes cellular and tissue damage. However, the role of nitrosation of SH groups in GSH, enzymes and other proteins in the pathogenesis of asbestos-induced diseases remains to be farther studied. In the present study, we focused on the extent of thiol-nitrosation with NO. RAW264.7 cells and J774 cells of murine macrophage cell lines were cultured with chrysotile B (CH) asbestos, crocidolite (CR) asbestos or MMMFs comprised of glass wool (GW), rock wool (RW) or ceramic (RF1). All of these fibers significantly increased NO production and RS-NO formation in the culture with macrophages. CH, CR and GW significantly decreased the level of GSH in RAW264.7 cells. A large portion of the increased RS-NO may be in the form of GS-NO, because GSH is the most abundant thiol substance in the cell. These results indicate that macrophages exposed to asbestos or MMMFs are subject to oxidative stress not only through the generation of ROS and RNS, but also through decreases in the level of the cellular antioxidant, GSH, by GS-NO formation. The increase of RS-NO in macrophages exposed to asbestos or MMMFs may deserve more attention as the indicator of continuous oxidative stress on cells and tissues, which causes inflammation and involves the development of asbestos-induced diseases. |