Iron in Lung Pathology

Zhang, Vida; Nemeth, Elizabeta; Kim, Airie

doi:10.3390/ph12010030

Cited by 36 publications

(33 citation statements)

References 77 publications

(90 reference statements)

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“…In lung FPN1 is facing the lumen of the alveoli and this localization has been attributed to a role in iron detoxification (10). Indeed, environmental iron arriving to the lung epithelium can be initially buffered by the activity of the antioxidant molecules such as ascorbic acid, reduced glutathione, and mucin, and once loaded on transferrin and lactoferrin herein present, it can undergo transferrin receptor 1 (TfR1) and lactoferrin receptor (LfR) internalization by epithelial alveolar cells and alveolar macrophages and be safely stored bound to ferritin (28). Under iron overload condition the excess of pulmonary iron can be release into the lumen of the alveoli via FPN1 permease and possibly oxidize by GPI-anchored or soluble ceruloplasmin, an HEPH homologue ferroxidase (29).…”

Section: Discussionmentioning

confidence: 99%

The ferroxidase HEPHaestin in Lung cancer: Pathological Significance and Prognostic Value

Zacchi

Belmonte

Mangogna

et al. 2021

Preprint

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Iron is a fundamental nutrient utilized by living cells to support several key cellular processes. Despite its paramount role to sustain cell survival, excess of labile iron availability can inflict severe cell damage via reactive oxygen species generation which, in turn, can promote neoplastic transformation. The lung is particularly sensitive to iron-induced oxidative stress, given the high oxygen tensions herein present. Moreover, cigarette smoke as well as air pollution particulate can function as vehicles of iron supply, leading to an iron dysregulation condition shown to be crucial in the pathogenesis of several respiratory diseases including lung cancer. Hephaestin (HEPH) belongs to a group of exocytoplasmic ferroxidases emerged to contribute to cellular iron homeostasis by favouring its export. Although HEPH can affect the concentration of intracellular iron labile pool, its expression in lung cancer and its influence on prognosis have not been investigated.In this study we explored the expression pattern and prognostic value of HEPH in the most prevalent histotypes of lung cancers including lung adenocarcinoma and lung squamous cell carcinoma across in silico analyses using UALCAN, Gepia and Kaplan-Meier plotter bioninformatics. We took advantage of TIMER to assess the correlation between HEPH and tumour infiltrating immune and non-immune cells. Then we performed immunohistochemical analysis to dissect the presence of HEPH either in “healthy” and tumor lung tissues. Overall, our data suggest a positive correlation between higher level of HEPH expression with a favorable prognosis in both cancer histotypes.

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Section: Discussionmentioning

confidence: 99%

The ferroxidase HEPHaestin in Lung cancer: Pathological Significance and Prognostic Value

Zacchi

Belmonte

Mangogna

et al. 2021

Preprint

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“…Interestingly, increased lung iron levels have been reported in several lung diseases and are associated with increased susceptibility to pulmonary infections ( Reid et al, 2007 ; Ali et al, 2017 ). As infectious complications are often the primary cause or opportunistic side-effects in respiratory syndromes it is of clinical relevance to understand the role of the host iron status ( Zhang et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Mild Attenuation of the Pulmonary Inflammatory Response in a Mouse Model of Hereditary Hemochromatosis Type 4

et al. 2021

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The respiratory tract is constantly exposed to pathogens that require iron for proliferation and virulence. Pulmonary iron levels are increased in several lung diseases and associated with increased susceptibility to infections. However, regulation of lung iron homeostasis and its cross talk to pulmonary immune responses are largely unexplored. Here we investigated how increased lung iron levels affect the early pulmonary inflammatory response. We induced acute local pulmonary inflammation via aerosolized LPS in a mouse model of hereditary hemochromatosis type 4 (Slc40a1C326S/C326S), which is hallmarked by systemic and pulmonary iron accumulation, specifically in alveolar macrophages. We show that Slc40a1C326S/C326S mice display a mild attenuation in the LPS-induced pulmonary inflammatory response, with a reduced upregulation of some pro-inflammatory cytokines and chemokines. Despite mildly reduced cytokine levels, there is no short-term impairment in the recruitment of neutrophils into the bronchoalveolar space. These data suggest that increased pulmonary iron levels do not strongly alter the acute inflammatory response of the lung.

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“…Similarly, altered iron metabolism was also described in multiple pulmonary diseases including chronic obstructive pulmonary disease (COPD). In the latter one, levels of iron and iron-binding proteins in the lung are increased with normal to reduced systemic iron availability [21,22,23,24]. Moreover, elevated levels of systemic iron are toxic to the lungs and correlate with disease severity and worsening lung function [25,26].…”

Section: Introductionmentioning

confidence: 99%

Mild Iron Overload as Seen in Individuals Homozygous for the Alpha-1 Antitrypsin Pi*Z Variant Does Not Promote Liver Fibrogenesis in HFE Knockout Mice

Güldiken

Hamesch

Schuller

et al. 2019

Cells

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The presence of the homozygous ‘Pi*Z’ variant of alpha-1 antitrypsin (AAT) (‘Pi*ZZ’ genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene (HFE) as the major cause of hereditary iron overload in a large cohort of Pi*ZZ subjects without liver comorbidities. The human cohort comprised of 409 Pi*ZZ individuals and 254 subjects without evidence of an AAT mutation who were recruited from ten European countries. All underwent a comprehensive work-up and transient elastography to determine liver stiffness measurements (LSM). The corresponding mouse models (Pi*Z overexpressors, HFE knockouts, and double transgenic [DTg] mice) were used to evaluate the impact of mild iron overload on Pi*Z-induced liver injury. Compared to Pi*Z non-carriers, Pi*ZZ individuals had elevated serum iron, transferrin saturation, and ferritin levels, but relevant iron overload was rare. All these parameters were higher in individuals with signs of significant liver fibrosis (LSM ≥ 7.1 kPa) compared to those without signs of significant liver fibrosis. HFE knockout and DTg mice displayed similar extent of iron overload and of fibrosis. Loss of HFE did not alter the extent of AAT accumulation. In Pi*ZZ individuals, presence of HFE mutations was not associated with more severe liver fibrosis. Taken together, Pi*ZZ individuals display minor alterations in serum iron parameters. Neither mild iron overload seen in these individuals nor the presence of HFE mutations (C282Y and H63D) constitute a major contributor to liver fibrosis development.

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Iron in Lung Pathology

Cited by 36 publications

References 77 publications

The ferroxidase HEPHaestin in Lung cancer: Pathological Significance and Prognostic Value

The ferroxidase HEPHaestin in Lung cancer: Pathological Significance and Prognostic Value

Mild Attenuation of the Pulmonary Inflammatory Response in a Mouse Model of Hereditary Hemochromatosis Type 4

Mild Iron Overload as Seen in Individuals Homozygous for the Alpha-1 Antitrypsin Pi*Z Variant Does Not Promote Liver Fibrogenesis in HFE Knockout Mice

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