Deficiency in the divalent metal transporter 1 increases bleomycin-induced lung injury |
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Authors: | Funmei Yang Jacqueline G Stonehuerner Judy H Richards Ngoc-Bich Nguyen Kimberly D Callaghan David J Haile Andrew J Ghio |
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Institution: | (1) Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229, USA;(2) Department of Medicine, The University of Texas Health Science Center, San Antonio, TX 78229, USA;(3) National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park, NC 27711, USA;(4) Human Studies Facility, Campus Box 7315, 104 Mason Farm Road, Chapel Hill, NC 27599-7315, USA; |
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Abstract: | Exposure to bleomycin can result in an inflammatory lung injury. The biological effect of this anti-neoplastic agent is dependent
on its coordination of iron with subsequent oxidant generation. In lung cells, divalent metal transporter 1 (DMT1) can participate
in metal transport resulting in control of an oxidative stress and tissue damage. We tested the postulate that metal import
by DMT1 would participate in preventing lung injury after exposure to bleomycin. Microcytic anemia (mk/mk) mice defective in DMT1 and wild-type mice were exposed to either bleomycin or saline via intratracheal instillation and
the resultant lung injury was compared. Twenty-four h after instillation, the number of neutrophils and protein concentrations
after bleomycin exposure were significantly elevated in the mk/mk mice relative to the wild-type mice. Similarly, levels of a pro-inflammatory mediator were significantly increased in the
mk/mk mice relative to wild-type mice following bleomycin instillation. Relative to wild-type mice, mk/mk mice demonstrated lower non-heme iron concentrations in the lung, liver, spleen, and splenic, peritoneal, and liver macrophages.
In contrast, levels of this metal were elevated in alveolar macrophages from mk/mk mice. We conclude that DMT1 participates in the inflammatory lung injury after bleomycin with mk/mk mice having increased inflammation and damage following exposure. This finding supports the hypothesis that DMT1 takes part
in iron detoxification and homeostasis in the lung. |
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