Submitted on October 27, 2005
Accepted on January 13, 2006
Manganese and Iron Transport Across Pulmonary Epithelium
Elizabeth A Heilig1, Khristy J Thompson2, Ramon M Molina3, Alexander R Ivanov4, Joseph D Brain3, and Marianne Wessling-Resnick2*
1 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA; Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA
2 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA
3 Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA
4 Harvard NIEHS Center for Environmental Health Proteomics Facility, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: wessling{at}hsph.harvard.edu.
Pathways mediating pulmonary metal uptake remain unknown. Because absorption of iron and manganese could involve similar mechanisms, transferrin (Tf) and transferrin receptor (TfR) expression in rat lungs was examined. Tf mRNA was detected in bronchial epithelium, Type II alveolar cells, macrophages and bronchus-associated lymphoid tissue (BALT). Tf protein levels in lung and bronchoalveolar lavage fluid did not change in iron deficiency despite increased plasma levels, suggesting that lung Tf concentrations are regulated by local synthesis in a manner independent of body iron status. Iron oxide exposure up-regulated Tf mRNA in bronchial and alveolar epithelium, macrophages and BALT, but protein was not significantly increased. In contrast, TfR mRNA and protein were both upregulated by iron deficiency. To examine potential interactions with lung Tf, rats were intratracheally instilled with 54Mn or 59Fe. Unlike 59Fe, interactions between 54Mn and Tf in lung fluid were not detected. Absorption of intratracheally-instilled 54Mn from the lungs to the blood was unimpaired in Belgrade rats homozygous for the functionally defective G185R allele of Divalent Metal Transporter-1 (DMT1), indicating that this transporter is also not involved in pulmonary manganese absorption. Pharmacological studies of 54Mn uptake by A549 cells suggest that metal uptake by Type II alveolar epithelial cells is associated with activities of both L-type Ca2+ channels and TRPM7, a member of the Transient Receptor Potential Melastatin subfamily These results demonstrate that iron and manganese are absorbed by the pulmonary epithelium through different pathways, and reveal the potential role for nonselective calcium channels in lung metal clearance.
