Lung injury after ozone exposure is iron dependent

2007 ◽  
Vol 292 (1) ◽  
pp. L134-L143 ◽  
Author(s):  
Andrew J. Ghio ◽  
Jennifer L. Turi ◽  
Michael C. Madden ◽  
Lisa A. Dailey ◽  
Judy D. Richards ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Injury ◽  
Iron Homeostasis ◽  
Biological Effects ◽  
Ozone Exposure ◽  
Divalent Metal Transporter 1 ◽  
Hek 293 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Elevated Expression

We tested the hypothesis that oxidative stress and biological effect after ozone (O3) exposure are dependent on changes in iron homeostasis. After O3 exposure, healthy volunteers demonstrated increased lavage concentrations of iron, transferrin, lactoferrin, and ferritin. In normal rats, alterations of iron metabolism after O3 exposure were immediate and preceded the inflammatory influx. To test for participation of this disruption in iron homeostasis in lung injury following O3 inhalation, we exposed Belgrade rats, which are functionally deficient in divalent metal transporter 1 (DMT1) as a means of iron uptake, and controls to O3. 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 O3 than in HBE cells exposed to filtered air. Aldehyde generation and IL-8 release by the HBE cells was also elevated following O3 exposure. Human embryonic kidney (HEK 293) cells with elevated expression of a DMT1 construct were exposed to filtered air and O3. With exposure to O3, 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 O3 exposure.

scholarly journals Skeletal Lipocalin-2 Is Associated with Iron-Related Oxidative Stress in ob/ob Mice with Sarcopenia

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 758
Author(s):  
Eun Bee Choi ◽  
Jae Hun Jeong ◽  
Hye Min Jang ◽  
Yu Jeong Ahn ◽  
Kyu Hyeon Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Iron Homeostasis ◽  
Skeletal Muscle Regeneration ◽  
Lipocalin 2 ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Candidate Target ◽  
And Oxidative Stress

Obesity and insulin resistance accelerate aging-related sarcopenia, which is associated with iron load and oxidative stress. Lipocalin-2 (LCN2) is an iron-binding protein that has been associated with skeletal muscle regeneration, but details regarding its role in obese sarcopenia remain unclear. Here, we report that elevated LCN2 levels in skeletal muscle are linked to muscle atrophy-related inflammation and oxidative stress in leptin-deficient ob/ob mice. RNA sequencing analyses indicated the LCN2 gene expression is enhanced in skeletal muscle of ob/ob mice with sarcopenia. In addition to muscular iron accumulation in ob/ob mice, expressions of iron homeostasis-related divalent metal transporter 1, ferritin, and hepcidin proteins were increased in ob/ob mice compared to lean littermates, whereas expressions of transferrin receptor and ferroportin were reduced. Collectively, these findings demonstrate that LCN2 functions as a potent proinflammatory factor in skeletal muscle in response to obesity-related sarcopenia and is thus a therapeutic candidate target for sarcopenia treatment.

Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4861-4864 ◽  
Author(s):  
Lydie Viatte ◽  
Jeanne-Claire Lesbordes-Brion ◽  
Dan-Qing Lou ◽  
Myriam Bennoun ◽  
Gaël Nicolas ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Homeostasis ◽  
Genetic Disorder ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
The Common ◽  
Related Proteins ◽  
Deficient Mice

Abstract Evidence is accumulating that hepcidin, a liver regulatory peptide, could be the common pathogenetic denominator of all forms of iron overload syndromes including HFE-related hemochromatosis, the most prevalent genetic disorder characterized by inappropriate iron absorption. To understand the mechanisms whereby hepcidin controls iron homeostasis in vivo, we have analyzed the level of iron-related proteins by Western blot and immunohistochemistry in hepcidin-deficient mice, a mouse model of severe hemochromatosis. These mice showed important increased levels of duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), and ferroportin compared with control mice. Interestingly, the level of ferroportin was coordinately up-regulated in the duodenum, the spleen, and the liver (predominantly in the Kupffer cells). Finally, we also evidenced a decrease of ceruloplasmin in the liver of hepcidin-deficient mice. We hypothesized that the deregulation of these proteins might be central in the pathogenesis of iron overload, providing key therapeutic targets for iron disorders. (Blood. 2005;105:4861-4864)

scholarly journals Influence of DMT1 and iron status on inflammatory responses in the lung

2011 ◽  
Vol 300 (4) ◽  
pp. L659-L665 ◽  
Author(s):  
Jonghan Kim ◽  
Ramon M. Molina ◽  
Thomas C. Donaghey ◽  
Peter D. Buckett ◽  
Joseph D. Brain ◽  
...  
Keyword(s):  
Lung Injury ◽  
Inflammatory Responses ◽  
Iron Status ◽  
Pulmonary Inflammation ◽  
Intratracheal Instillation ◽  
Cell Content ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter

Divalent metal transporter 1 (DMT1) is the major iron transporter responsible for duodenal dietary iron absorption and is required for erythropoiesis. Recent studies suggest that loss of DMT1 activity could be involved in metal-related lung injury, but little is known about the effects of iron status and DMT1 function on pulmonary inflammation. To better define the role of DMT1 and iron status in pulmonary inflammatory responses, we performed bronchoalveolar lavage (BAL) following intratracheal instillation of lipopolysaccharide (LPS) to the Belgrade rat, an animal model deficient in DMT1 function. In the basal state, the BAL fluid of Belgrade rats had more macrophages and higher lactate dehydrogenase, myeloperoxidase, albumin, and hemoglobin levels compared with heterozygote control rats. Following LPS instillation, the macrophage fraction relative to total BAL cell content and levels of albumin and IgM were increased in Belgrade rats compared with controls. In contrast, heterozygote Belgrade rats made anemic by diet-induced iron deficiency exhibited attenuated inflammatory responses to LPS. These combined results show that pulmonary inflammation can be modified by both DMT1 and iron status. Loss of DMT1 alters pulmonary responses necessary for lung homeostasis in the basal state and enhances LPS-induced inflammation and therefore would contribute to progression of lung injury.

scholarly journals Decreased hepatic iron in response to alcohol may contribute to alcohol-induced suppression of hepcidin

2016 ◽  
Vol 115 (11) ◽  
pp. 1978-1986 ◽  
Author(s):  
Joe Varghese ◽  
Jithu Varghese James ◽  
Sreerohini Sagi ◽  
Subhosmito Chakraborty ◽  
Abitha Sukumaran ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Time Course ◽  
Histopathological Examination ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Hepcidin Expression ◽  
Cytochrome P4502e1 ◽  
Metal Transporter ◽  
Serum Hepcidin ◽  
Time Course Study

AbstractHepatic Fe overload has often been reported in patients with advanced alcoholic liver disease. However, it is not known clearly whether it is the effect of alcohol that is responsible for such overload. To address this lacuna, a time-course study was carried out in mice in order to determine the effect of alcohol on Fe homoeostasis. Male Swiss albino mice were pair-fed Lieber–DeCarli alcohol diet (20 % of total energy provided as alcohol) for 2, 4, 8 or 12 weeks. Expression levels of duodenal and hepatic Fe-related proteins were determined by quantitative PCR and Western blotting, as were Fe levels and parameters of oxidative stress in the liver. Alcohol induced cytochrome P4502E1 and oxidative stress in the liver. Hepatic Fe levels and ferritin protein expression dropped to significantly lower levels after 12 weeks of alcohol feeding, with no significant effects at earlier time points. This was associated, at 12 weeks, with significantly decreased liver hepcidin expression and serum hepcidin levels. Protein expressions of duodenal ferroportin (at 8 and 12 weeks) and divalent metal transporter 1 (at 8 weeks) were increased. Serum Fe levels rose progressively to significantly higher levels at 12 weeks. Histopathological examination of the liver showed mild steatosis, but no stainable Fe in mice fed alcohol for up to 12 weeks. In summary, alcohol ingestion by mice in this study affected several Fe-related parameters, but produced no hepatic Fe accumulation. On the contrary, alcohol-induced decreases in hepatic Fe levels were seen and may contribute to alcohol-induced suppression of hepcidin.

Iron increases expression of iron-export protein MTP1 in lung cells

2002 ◽  
Vol 283 (5) ◽  
pp. L932-L939 ◽  
Author(s):  
Funmei Yang ◽  
Xinchao Wang ◽  
David J. Haile ◽  
Claude A. Piantadosi ◽  
Andrew J. Ghio
Keyword(s):  
Protein Level ◽  
Iron Homeostasis ◽  
Tissue Injury ◽  
Fold Increase ◽  
Lung Cells ◽  
Mrna Levels ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Lung Defense

Accumulation of reactive iron in acute and chronic lung disease suggests that iron-driven free radical formation could contribute to tissue injury. Safe transport and sequestration of this metal is likely to be of importance in lung defense. We provide evidence for the expression and iron-induced upregulation of the metal transporter protein-1 (MTP1) genes in human and rodent lung cells at both the protein and mRNA levels. In human bronchial epithelial cells, a 3.8-fold increase in mRNA level and a 2.4-fold increase in protein level of MTP1 were observed after iron exposure. In freshly isolated human macrophages, as much as an 18-fold increase in the MTP1 protein level was detected after incubation with an iron compound. The elevation in expression of MTP1 gene was also demonstrated in iron-instilled rat lungs and in hypotransferrinemic mouse lungs. This is similar to our previous findings with divalent metal transporter-1 (DMT1), an iron transporter that is required for iron uptake and intracellular iron trafficking. These studies suggest the presence of iron mobilization and/or detoxification pathways in the lung that are crucial for iron homeostasis and lung defense.

Role of the kidney in iron homeostasis: renal expression of Prohepcidin, Ferroportin, and DMT1 in anemic mice

2008 ◽  
Vol 295 (4) ◽  
pp. F1213-F1221 ◽  
Author(s):  
Tania Veuthey ◽  
María Cecilia D'Anna ◽  
Marta Elena Roque
Keyword(s):  
Hemolytic Anemia ◽  
Iron Homeostasis ◽  
Renal Medulla ◽  
Renal Tissue ◽  
Proximal Tubules ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Tissue Iron ◽  
Renal Expression

It is known that renal tissue plays a role in normal iron homeostasis. The current study examines kidney function in iron metabolism under hemolytic anemia studying renal expression of Prohepcidin, Ferroportin (MTP1), and divalent metal transporter 1 (DMT1). The relationship between these proteins and iron pigments was also investigated. Immunohistochemical procedures to study renal expression of Prohepcidin, MTP1, and DMT1 were performed in healthy and anemic mice. Renal tissue iron was determined by Prussian blue iron staining. To assess anemia evolution and erythropoietic recovery, we used conventional tests. In healthy mice, Prohepcidin expression was marked in proximal tubules and inner medulla and absent in outer medulla. Cortical tissue of healthy mice also showed MTP1 immunostaining, mainly in the S2 segment of proximal tubules. Medullar tissue showed MTP1 expression in the inner zone. In addition, S2 segments showed intense DMT1 immunoreactivity with homogeneous DMT1 distribution throughout renal medulla. The main cortical findings in hemolytic anemia were in S2 segments of proximal tubules where we found that decreased Prohepcidin expression coincided with an increment in Ferroportin and DMT1 expression. This expression pattern was concomitant with increased iron in the same tubular zone. However, in medullar tissue both Prohepcidin and MTP1 decreased and DMT1 was detected mainly in larger diameter tubules. Our findings clearly demonstrate that in hemolytic anemia, renal Prohepcidin acts in coordination with renal Ferroportin and DMT1, indicating the key involvement of kidney in iron homeostasis when iron demand is high. Further research is required to learn more about these regulatory mechanisms.

scholarly journals Intestinal ferritinophagy is regulated by HIF-2α and is essential for systemic iron homeostasis

2020 ◽  
Author(s):  
Nupur K Das ◽  
Amanda Sankar ◽  
Andrew J Schwartz ◽  
Sumeet Solanki ◽  
Xiaoya Ma ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Whole Body ◽  
Null Mouse ◽  
Divalent Metal Transporter 1 ◽  
Intestinal Iron Absorption ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Iron Sequestration

AbstractIron is critical for many processes including oxygen transport and erythropoiesis. Transcriptomic analysis demonstrates that HIF-2α regulates over 90% of all transcripts induced following iron deficiency in the intestine. However, beyond divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1) and duodenal cytochrome b (Dcytb), no other genes/pathways have been critically assessed with respects to their importance in intestinal iron absorption. Ferritinophagy is associated with cargo specific autophagic breakdown of ferritin and subsequent release of iron. We show here that nuclear receptor co-activator 4 (NCOA4)-mediated intestinal ferritinophagy is integrated to systemic iron demand via HIF-2α. Duodenal NCOA4 expression is regulated by HIF-2α during high systemic iron demands. Moreover, overexpression of intestinal HIF-2α is sufficient to activate NCOA4 and promote lysosomal degradation of ferritin. Promoter analysis revealed NCOA4 as a direct HIF-2α target. To demonstrate the importance of intestinal HIF-2α/ferritinophagy axis in systemic iron homeostasis, whole body and intestine-specific NCOA4-null mouse lines were assessed. These analyses demonstrate an iron sequestration in the enterocytes, and significantly high tissue ferritin levels in the dietary iron deficiency and acute hemolytic anemia models. Together, our data suggests efficient ferritinophagy is critical for intestinal iron absorption and systemic iron homeostasis.

Deficiency in the divalent metal transporter 1 increases bleomycin-induced lung injury

BioMetals ◽  
2010 ◽  
Vol 23 (4) ◽  
pp. 657-667 ◽  
Author(s):  
Funmei Yang ◽  
Jacqueline G. Stonehuerner ◽  
Judy H. Richards ◽  
Ngoc-Bich Nguyen ◽  
Kimberly D. Callaghan ◽  
...  
Keyword(s):  
Lung Injury ◽  
Divalent Metal ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter

scholarly journals Antioxidant Effect of Propofol in Gliomas and Its Association With Divalent Metal Transporter 1

2020 ◽  
Vol 10 ◽  
Author(s):  
Chenyi Yang ◽  
Zhengyuan Xia ◽  
Tang Li ◽  
Yimeng Chen ◽  
Mingshu Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Ampa Receptor ◽  
Glioma Cells ◽  
Divalent Metal ◽  
Oxygen Species ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter

BackgroundOxidative stress enhances tumor invasion and metastasis in brain cancer. The activation of divalent metal transporter 1 (DMT1), which is regulated by glutamate receptors, can result in the increase of oxidative stress and risk of cancer development. Propofol, an anesthetic with antioxidant capacity, has been shown to decrease oxidative stress in several different types of cancer. However, the underlying mechanism remains unclear. Therefore, the present study aimed to elucidate the mechanism underlying the suppression of oxidative stress in glioma cells by propofol. It was hypothesized that propofol may inhibit oxidative stress in gliomas via suppressing Ca2+-permeable α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA) receptor (CPAR)-DMT1 signaling.MethodsMale Wistar rats with C6 gliomas, which were established by intracranial injection of C6 glioma cells, were either treated with propofol or not for 6 h before being sacrificed. The levels of AMPA receptor subunit GluR2 and DMT1 protein expression were assessed using western blotting. The association between CPARs and DMT1 was confirmed in vitro using the AMPA receptor activator (R, S)-AMPA. Glutathione and reactive oxygen species assay kits were used to evaluate tumor oxidative stress. The effect of propofol on glioma proliferation was evaluated by determining tumor weight, cell cycles and a growth curve.ResultsPropofol infusion at either 20 or 40 mg/kg-1/h-1 increased GluR2 levels and downregulated DMT1 expression as well as glutathione content markedly in the periphery compared with that in the glioma core. The in vitro results revealed that (R, S)-AMPA increased DMT1 expression and reactive oxygen species levels, which were partly reversed by propofol treatment.ConclusionPropofol regulated DMT1 expression by modulating CPARs, resulting in the inhibition of tumor oxidative stress and glioma growth. The present study provides evidence for optimizing the selection of anesthetic drugs in perioperative management and prognosis of patients with glioma.

Sign in / Sign up

Export Citation Format

Share Document