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We tested the hypothesis that oxidative stress and biological effect after ozone ([O.sub.3]) exposure are dependent on changes in iron homeostasis. After [O.sub.3] exposure, healthy volunteers demonstrated increased lavage concentrations of iron, transferrin, lactoferrin, and ferritin. In normal rats, alterations of iron metabolism after [O.sub.3] exposure were immediate and preceded the inflammatory influx. To test for participation of this disruption in iron homeostasis in lung injury following [O.sub.3] inhalation, we exposed Belgrade rats, which are functionally deficient in divalent metal transporter 1 (DMT1) as a means of iron uptake, and controls to [O.sub.3]. Iron homeostasis was disrupted to a greater extent and the extent of injury was greater in Belgrade rats than in control rats. Nonheme iron and ferritin concentrations were higher in human bronchial epithelial (HBE) cells exposed to [O.sub.3] than in HBE cells exposed to filtered air. Aldehyde generation and IL-8 release by the HBE cells was also elevated following [O.sub.3] exposure. Human embryonic kidney (HEK 293) cells with elevated expression of a DMT1 construct were exposed to filtered air and [O.sub.3]. With exposure to [O.sub.3], elevated DMT1 expression diminished oxidative stress (i.e., aldehyde generation) and IL-8 release. We conclude that iron participates critically in the oxidative stress and biological effects after [O.sub.3] exposure. air pollution; lung diseases; ferritin; oxidants; free radicals

Ghio, Andrew J., Claude A. Piantadosi, Xinchao Wang, Lisa A. Dailey, Jacqueline D. Stonehuerner, Michael C. Madden, Funmei Yang, Kevin G. Dolan, Michael D. Garrick, and Laura M. Garrick. Divalent metal transporter-1 decreases metal-related injury in the lung. Am J Physiol Lung Cell Mol Physiol 289: L460-L467, 2005. First published May 20, 2005: doi:10.1152/ajplung.00154.2005.--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

Ferroportin 1 (FPN1; aka MTP1, IREG1, and SLC40A1), which was originally identified as a basolateral iron transporter crucial for nutritional iron absorption in the intestine, is expressed in airway epithelia and upregulated when these cells are exposed to iron. Using immunofluorescence labeling and confocal microscopic imaging techniques, we demonstrate that in human and rodent lungs, FPN1 localizes subcellularly to the apical but not basolateral membrane of the airway epithelial cells. The role of airway epithelial cells in iron mobilization in the lung was studied in an in vitro model of the polarized airway epithelium. Normal human bronchial epithelial cells, grown on membrane supports until differentiated, were exposed to iron, and the efficiency and direction of iron transportation were studied. We found that these cells can efficiently take up iron across the apical but not basolateral surface in a concentration-dependent manner. Most of the iron taken up by the cells is then released into the medium within 8 h in the form of less reactive protein-bound complexes including ferritin and transferrin. Interestingly, iron release also occurred across the apical but not basolateral membrane. Our findings indicate that FPN1, depending on its subcellular location, could have distinct functions in iron homeostasis in different cells and tissues. Although it is responsible for exporting nutrient iron from enterocytes to the circulation in the intestine, it could play a role in iron detoxification in airway epithelial cells in the lung. iron metabolism; divalent metal transporter-l; ferritin; transferrin

The iron chelator deferoxamine has been reported to inhibit both xanthine oxidase (XO) and xanthine dehydrogenase activity, but the relationship of this effect to the availability of iron in the cellular and tissue environment remains unexplored. XO and total xanthine oxidoreductase activity in cultured V79 cells was increased with exposure to ferric ammonium sulfate and inhibited by deferoxamine. Lung XO and total xanthine oxidoreductase activities were reduced in rats fed an iron-depleted diet and increased in rats supplemented with iron, without change in the ratio of XO to total oxidoreductase. Intratracheal injection of an iron salt or silica-iron, but not aluminum salts or silica-zinc, significantly increased rat lung XO and total xanthine oxidoreductase activities, immunoreactive xanthine oxidoreductase, and the concentration of urate in bronchoalveolar fluid. These results suggest the possibility that the production of uric acid, a major chelator of iron in extracellular fluid, is directly influenced by iron-mediated regulation of the expression and/or activity of its enzymatic source, xanthine oxidase. xanthine dehydrogenase; deferoxamine; silica; uric acid

Partial combustion of tobacco deposits humic-like substances (HLS) as pigment particles in lung and complex iron cations in vivo and vitro regions that catalyze oxidant formation. The deposits are identified from cigarette smoke condensate (CSC) in lung tissues. Oxidant formation depends on metal, with the HLS and iron cations generating free radicals. The results confirm the pathogenic effect on HLS that causes lung diseases due to continuous cigarette exposure.

Abstract Background Lung injury caused by both inhaled dusts and infectious agents depends on increased availability of iron and metal-catalyzed oxidative stress. Because inhaled particles, such as silica, and certain infections can cause secondary pulmonary alveolar proteinosis (PAP), we tested the hypothesis that idiopathic PAP is associated with an altered iron homeostasis in the human lung. Methods Healthy volunteers (n = 20) and patients with idiopathic PAP (n = 20) underwent bronchoalveolar lavage and measurements were made of total protein, iron, tranferrin, transferrin receptor, lactoferrin, and ferritin. Histochemical staining for iron and ferritin was done in the cell pellets from control subjects and PAP patients, and in lung specimens of patients without cardiopulmonary disease and with PAP. Lavage concentrations of urate, glutathione, and ascorbate were also measured as indices of oxidative stress. Results Lavage concentrations of iron, transferrin, transferrin receptor, lactoferrin, and ferritin were significantly elevated in PAP patients relative to healthy volunteers. The cells of PAP patients had accumulated significant iron and ferritin, as well as considerable amounts of extracellular ferritin. Immunohistochemistry for ferritin in lung tissue revealed comparable amounts of this metal-storage protein in the lower respiratory tract of PAP patients both intracellularly and extracellularly. Lavage concentrations of ascorbate, glutathione, and urate were significantly lower in the lavage fluid of the PAP patients. Conclusion Iron homeostasis is altered in the lungs of patients with idiopathic PAP, as large amounts of catalytically-active iron and low molecular weight anti-oxidant depletion are present. These findings suggest a metal-catalyzed oxidative stress in the maintenance of this disease.

Ferroportin 1 (FPN 1; aka MTP1, IREG1, and SLC40A1), which was originally identified as a basolateral iron transporter crucial for nutritional iron absorption in the intestine, is expressed in airway epithelia and upregulated when these cells are exposed to iron. Using immunofluorescence labeling and confocal microscopic imaging techniques, we demonstrate that in human and rodent lungs, FPN1 localizes subcellularly to the apical but not basolateral membrane of the airway epithelial cells. The role of airway epithelial cells in iron mobilization in the lung was studied in an in vitro model of the polarized airway epithelium. Normal human bronchial epithelial cells, grown on membrane supports until differentiated, were exposed to iron, and the efficiency and direction of iron transportation were studied. We found that these cells can efficiently take up iron across the apical but not basolateral surface in a concentration-dependent manner. Most of the iron taken up by the cells is then released into the medium within 8 h in the form of less reactive protein-bound complexes including ferritin and transferrin. Interestingly, iron release also occurred across the apical but not basolateral membrane. Our findings indicate that FPN1, depending on its subcellular location, could have distinct functions in iron homeostasis in different cells and tissues. Although it is responsible for exporting nutrient iron from enterocytes to the circulation in the intestine, it could play a role in iron detoxification in airway epithelial cells in the lung. [ABSTRACT FROM AUTHOR]

One potential mechanism of injury mediated by air pollution particles is through metalcatalyzed oxidant generation. In one emission source particle, soluble metals have been associated with biological effect and toxicity. However, a majority of metals in ambient air pollution particles can be associated with insoluble components. We tested the hypothesis that concentrations of catalytically active metal in ambient air pollution particles are not equivalent to the concentrations of water-soluble metal. Twelve filters collected from the North Provo, UT, monitoring station were agitated in deionized water. Both the aqueous extract and pellet were isolated, lyophilized, and defined as the water-soluble and insoluble fractions, respectively. The fractions were chemically characterized and ionizable concentrations of metals were measured using inductively coupled plasma emission spectroscopy. While the water-soluble fraction had significantly greater concentrations of ionizable metals per unit mass, the insoluble fraction also had measurable quantities. In vitro oxidant generation by the two fractions, measured as thiobarbituric acid-reactive-products of deoxyribose, corresponded to the concentrations of ionizable rather than total metals. The release of interleukin-8 by cultured respiratory epithelial cells after incubation with the two fractions also coincided with the ionizable metal concentrations. Finally, neutrophil influx and lavage protein levels 24 h after instillation of the two fractions in rats reflected the ionizable metal concentrations, in vitro oxidative stress, and mediator release. We conclude that catalytically active metals can be measured in both the soluble and insoluble fractions of an ambient air pollution particle. These metals corresponded to the biological activity of the two fractions. While in greater concentration in the water-soluble fraction, larger total quantities of catalytically and biologically active metals are likely to be associated with the insoluble fraction as a result of the abundance of the latter. [ABSTRACT FROM AUTHOR]