Variable tissue expression of transferrin receptors: relevance to acute respiratory distress syndrome

Upton, Rebecca; Chen, Y.; Mumby, Sharon; Gutteridge, John M.C.; Anning, Peter B.; Nicholson, Andrew G.; Evans, Timothy W.; Quinlan, Gregory J.

doi:10.1183/09031936.03.00075302

Cited by 21 publications

(63 citation statements)

References 30 publications

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“…Importantly, increased expression of TfR1 has been observed in animal models of inflammation (2,18). In humans, direct evidence of TfR1 up-regulation has been recently found in patients with acute respiratory distress syndrome (18).…”

Section: Discussionmentioning

confidence: 92%

“…In humans, direct evidence of TfR1 up-regulation has been recently found in patients with acute respiratory distress syndrome (18). In addition, levels of soluble TfR receptor are associated with inflammation independent of the degree of erythropoiesis, the hypoxic response and iron status (48).…”

Section: Discussionmentioning

confidence: 99%

“…Thus far, the possibility that inflammation-mediated accumulation of iron in parenchymal cells may also contribute to hypoferremia has not received much attention. Nevertheless, the expression of transferrin receptor 1 (TfR1), 2 the major iron uptake protein, is induced in several models of inflammation (2,18).…”

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confidence: 99%

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Sustained Hydrogen Peroxide Induces Iron Uptake by Transferrin Receptor-1 Independent of the Iron Regulatory Protein/Iron-responsive Element Network

Andriopoulos

Hegedüsch

Mangin

et al. 2007

Journal of Biological Chemistry

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Local and systemic inflammatory conditions are characterized by the intracellular deposition of excess iron, which may promote tissue damage via Fenton chemistry. Because the Fenton reactant H 2 O 2 is continuously released by inflammatory cells, a tight regulation of iron homeostasis is required. Here, we show that exposure of cultured cells to sustained low levels of H 2 O 2 that mimic its release by inflammatory cells leads to upregulation of transferrin receptor 1 (TfR1), the major iron uptake protein. The increase in TfR1 results in increased transferrin-mediated iron uptake and cellular accumulation of the metal. Although iron regulatory protein 1 is transiently activated by H 2 O 2 , this response is not sufficient to stabilize TfR1 mRNA and to repress the synthesis of the iron storage protein ferritin. The induction of TfR1 is also independent of transcriptional activation via hypoxia-inducible factor 1␣ or significant protein stabilization. In contrast, pulse experiments with 35 Slabeled methionine/cysteine revealed an increased rate of TfR1 synthesis in cells exposed to sustained low H 2 O 2 levels. Our results suggest a novel mechanism of iron accumulation by sustained H 2 O 2 , based on the translational activation of TfR1, which could provide an important (patho)physiological link between iron metabolism and inflammation.Systemic iron homeostasis undergoes typical changes during inflammatory or infectious conditions. A decrease in plasma iron concentration limits the availability of the metal for erythropoiesis, ultimately leading to the so-called anemia of chronic disease (1). In addition to iron retention within the reticuloendothelial system, parenchymal cells such as hepatocytes also accumulate iron under inflammatory conditions (2-8), and this iron deposition has been identified as an important factor in tissue damage by free radicals (9). In addition, hepatic iron accumulation appears to be an important cofactor in the development of fibrosis and end stage liver disease in such common chronic liver pathologies such as hepatitis C or alcoholic steatohepatitis (4 -8).Significant progress has been made toward understanding the molecular basis of iron retention within the reticuloendothelial system during inflammation (10 -12). The mechanism involves the interleukin-6-mediated induction of the iron-regulatory peptide hepcidin (13, 14), which inhibits iron efflux from macrophages and intestinal enterocytes (15, 16) by binding to and promoting the degradation of the transporter ferroportin 1 (IREG1 or MTP1) (17). The ensuing hypoferremia is thought to be part of a physiological defense strategy to deplete invading bacteria from the growth-essential iron. Thus far, the possibility that inflammation-mediated accumulation of iron in parenchymal cells may also contribute to hypoferremia has not received much attention. Nevertheless, the expression of transferrin receptor 1 (TfR1), 2 the major iron uptake protein, is induced in several models of inflammation (2, 18).Upon activation, inflammatory cells su...

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Sustained Hydrogen Peroxide Induces Iron Uptake by Transferrin Receptor-1 Independent of the Iron Regulatory Protein/Iron-responsive Element Network

Andriopoulos

Hegedüsch

Mangin

et al. 2007

Journal of Biological Chemistry

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“…67 Ceruloplasmin is also present in pulmonary fluid and therefore could potentially oxidize Mn 12 for loading onto Tf. 68 Tf receptor expression in the lungs appears to respond to inflammation, 69,70 and exposure of lungs to ferric ammonium citrate upregulates DMT1 in an isoform specific manner. 71 As described earlier, all of these factors could play a role in clearance of inhaled manganese from the lungs.…”

Section: Hypothetical Model For Pulmonary Manganese Transportmentioning

confidence: 95%

Manganese Transport Across the Pulmonary Epithelium

Thompson¹,

Kim²,

Wessling‐Resnick³

2014

Manganese in Health and Disease

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Our lungs represent a significant exposure site to airborne metals. Manganese and other metals enter the bloodstream from a variety of airborne sources across the pulmonary epithelium. Once absorbed, manganese can be taken up by other organ systems like the brain, where it is known to exert neurotoxic effects. Models of pulmonary manganese absorption have been developed based on known pathways of uptake across the intestinal epithelium, which are regulated by iron status. The sum of evidence suggests that additional and perhaps unique transport pathways are available to manganese in order to transit the pulmonary epithelium. Both in vitro and in vivo models have been established to characterize not only the transport but also toxicity of manganese on pulmonary epithelial cells. Handling of manganese by the lungs plays an important role in the inflammatory response, and has a strong influence on lung infection. These issues and emerging new questions are discussed in this chapter.

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“…Also, the presence of ceruloplasmin in the pulmonary fluid can facilitate the oxidation of Mn +2 to Mn +3 which binds Tf [174]. Inflammation can affect TfR expression in the lungs, and DMT1 can be up-regulated as a result of exposure to ferric ammonium citrate [175]. All of these factors can affect Mn uptake from the lungs after Mn inhalation.…”

Section: Pulmonary Mn Uptakementioning

confidence: 99%

Effect of hemochromatosis on manganese neurotoxicity

Alsulimani¹

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ABSTRACT:Manganese (Mn) is an essential element for normal brain function, but excess levels of Mn in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. While Mn is known to share iron transporters for cellular uptake, deficiency in the Hfe (hemochromatosis), a cellular iron regulatory protein, affects the activities of iron transporters and impairs iron metabolism. Previously it was shown that Mn uptake into the brain is increased after intranasal exposure to Mn in Hfe-deficient mice, a mouse model of iron overload hereditary hemochromatosis. However, there is limited information about the effect of Hfe deficiency on Mn toxicity after exposure by other routes. Mn exposure is common through ingestion and inhalation in both environmental and occupational settings. Because Hfe deficiency alters iron transporters, and since Mn shares iron transporters, I hypothesize that Hfe deficiency increases Mn toxicity by modulating Mn uptake from the absorption site and deposition into the target organ for Mn toxicity which is the brain after gastric exposure in drinking water and pulmonary exposure to Mn particles. Specific aims are focused on the effect of Hfe deficiency on 1) the expression levels of metal transporters in the brain, gut and lung including alveolar macrophages, 2) levels of Mn, 3) Mn-associated neurobehavioral impairments, and 4) mechanisms of Mn neurotoxicity. This research will enhance the knowledge of Mn exposure and uptake in Hfe-related hemochromatosis, a prevalent iron disorder in the world.

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Variable tissue expression of transferrin receptors: relevance to acute respiratory distress syndrome

Cited by 21 publications

References 30 publications

Sustained Hydrogen Peroxide Induces Iron Uptake by Transferrin Receptor-1 Independent of the Iron Regulatory Protein/Iron-responsive Element Network

Sustained Hydrogen Peroxide Induces Iron Uptake by Transferrin Receptor-1 Independent of the Iron Regulatory Protein/Iron-responsive Element Network

Manganese Transport Across the Pulmonary Epithelium

Effect of hemochromatosis on manganese neurotoxicity

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