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Oxidant Generation Promotes Iron Sequestration in BEAS-2B Cells Exposed to Asbestos

Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina, Chapel Hill; National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park; Duke University Medical Center, Durham, North Carolina; and School of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China

Correspondence and requests for reprints should be addressed to Andrew J. Ghio, M.D., Campus Box 7315, Human Studies Division, U.S. EPA, 104 Mason Farm Road, Chapel Hill, NC 27599-7315. E-mail: ghio.andy{at}epa.gov

Lung injury after asbestos exposure is associated with an oxidative stress that is catalyzed by iron in the fiber matrix, complexed to the surface, or both. We tested the hypothesis that the cellular response to asbestos includes the transport and sequestration of this iron through (1) generation of superoxide for ferrireduction, (2) up-regulation of divalent metal transporter-1 (DMT1) for intracellular transport of Fe²⁺, and (3) increased production of cellular ferritin where the metal is stored in a catalytically less reactive state. BEAS-2B cells with normal and elevated Cu,Zn superoxide dismutase (SOD) expression were employed for in vitro investigations. After exposure of these cells to asbestos, we demonstrated by fluorescence methodology a significantly increased generation of SOD with ferrireductive capacity. Fiber exposure also increased DMT1 protein and mRNA expression in the BEAS-2B cells. Incubation with asbestos elevated cellular iron and ferritin concentrations, and these responses were diminished in cells with an enhanced expression of SOD. Finally, fiber exposure increased supernatant concentrations of interleukin 8, but this inflammatory mediator was actually increased in cells with elevated SOD expression. We conclude that the response of respiratory epithelial cells to asbestos includes oxidant-mediated mechanisms to sequester catalytically active iron associated with the fiber.

Key Words: Nramp2 • free radicals • lung diseases • ferritin