| Manganese in air pollution particles which deposit in the lungs is actively transported across the pulmonary epithelium, enters the blood stream, and can accumulate in the brain, resulting in neurotoxicity. This dissertation has explored mechanisms by which manganese is transported by pulmonary epithelial cells. In the duodenum, dietary iron and manganese are absorbed by a common transporter, divalent metal transporter 1 (DMT1). DMT1 is regulated by iron status, such that absorption of manganese from the diet is increased in iron deficiency and decreased in iron overload. To determine whether iron status would similarly affect transport of manganese across the air-blood barrier in the lungs, pharmacokinetics of pulmonary manganese transport was assessed in rat models of dietary iron deficiency and pulmonary iron overload. No significant change in lung 54Mn transport was observed in iron-deficiency; however altered blood clearance rates were observed, and were accounted for by increased 54Mn uptake by erythrocytes. In contrast, prior exposure to inhaled iron oxide particles resulted in decreased transport of both 54Mn and 59Fe across the air-blood barrier, suggestive of competition for common transporter(s).;To further characterize pathways for iron and manganese transport in the lungs, expression pattern, localization, and iron-responsiveness of expression were determined for DMT1, transferrin (Tf), and transferrin receptor 1 (TfR). DMT1, Tf, and TfR mRNAs are expressed in bronchial and alveolar epithelium, bronchus-associated lymphoid tissue (BALT), and alveolar macrophages. Increases in DMT1 and Tf expression were observed in iron oxide-exposed lungs. In contrast, TfR expression was upregulated in alveolar epithelium in iron-deficient rat lung, while expression of Tf and DMT1 did not change.;FPLC fractionation of in vivo-54Mn-labeled pulmonary fluid demonstrated that intratracheally instilled 54Mn did not significantly interact with Tf or other proteins in lung fluid, suggesting transport pathways for free manganese ions may be important for uptake by pulmonary epithelial cells. Pharmacological screening of 54Mn uptake by A549 cells identified L-type voltage-gated Ca2+ channel and TRPM7 as potential candidates for Mn2+ transport, while DMT1 did not appear to play a major role. In conclusion, multiple pathways including nonselective ion channels may be involved in manganese transport by pulmonary epithelial cells. |
