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Divalent metal transporter-1 decreases metal-related injury in the lung

¹National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park; ²Department of Medicine, Duke University Medical Center, Durham; ³Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill, North Carolina; ⁴Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas; and ⁵Department of Biochemistry, State University of New York, Buffalo, New York

Submitted 7 April 2005 ; accepted in final form 11 May 2005

Exposure to airborne particulates makes the detoxification of metals a continuous challenge for the lungs. Based on the fate of iron in airway epithelial cells, we postulated that divalent metal transporter-1 (DMT1) participates in detoxification of metal associated with air pollution particles. Homozygous Belgrade rats, which are functionally deficient in DMT1, exhibited diminished metal transport from the lower respiratory tract and greater lung injury than control littermates when exposed to oil fly ash. Preexposure of normal rats to iron in vivo increased expression of the isoform of DMT1 protein that lacked an iron-response element (–IRE), accelerated metal transport out of the lung, and decreased injury after particle exposure. In contrast, normal rats preexposed to vanadium showed less expression of the –IRE isoform of DMT1, decreased metal transport, and greater pulmonary injury after particle instillation. Respiratory epithelial cells in culture gave similar results. Also, DMT1 mRNA and protein expression for the –IRE isoform increased or decreased in these cells when exposed to iron or vanadium, respectively. These results thus demonstrate for the first time a primary role for DMT1 in lung metal transport and detoxification.

membrane transporters; metals; lung; divalent cation transporter-1; natural resistance-associated macrophage protein 2; SLC11A2

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