In Vitro Transformation of Human Bronchial Epithelial Cells by Diesel Exhaust Particles: Gene Expression Profiling and Early Toxic Responses

Rynning, Iselin; Neča, Jiřı́; Vrbová, Kristýna; Líbalová, Helena; Rössner, Pavel; Holme, Jørn A.; Gützkow, Kristine B.; Afanou, Anani; Arnoldussen, Yke Jildouw; Hrubá, Eva; Skare, Øivind; Haugen, Aage; Topinka, Jan; Machala, Miroslav; Mollerup, Steen

doi:10.1093/toxsci/kfy183

Cited by 23 publications

(30 citation statements)

References 60 publications

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“…The only exception was the increase in PGD 2 and the decrease in PGE 2 metabolites, which may suggest a slight induction of anti-inflammatory response [30] at low, non-cytotoxic concentration of PM0.5. Importantly, we found no significant modulation of levels of 8-iso-PGF 2alpha , 9-and 13-HODE, the markers of oxidative stress and lipid peroxidation [29,55], although oxidative stress is generally a well-accepted mechanism of nanoparticle-induced toxicity (e.g., [56]).…”

Section: Discussioncontrasting

confidence: 53%

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Screening of Cellular Stress Responses Induced by Ambient Aerosol Ultrafine Particle Fraction PM0.5 in A549 Cells

Šimečková¹,

Marvanová²,

Kulich³

et al. 2019

IJMS

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Effects of airborne particles on the expression status of markers of cellular toxic stress and on the release of eicosanoids, linked with inflammation and oxidative damage, remain poorly characterized. Therefore, we proposed a set of various methodological approaches in order to address complexity of PM0.5-induced toxicity. For this purpose, we used a well-characterized model of A549 pulmonary epithelial cells exposed to a non-cytotoxic concentration of ambient aerosol particle fraction PM0.5 for 24 h. Electron microscopy confirmed accumulation of PM0.5 within A549 cells, yet, autophagy was not induced. Expression profiles of various cellular stress response genes that have been previously shown to be involved in early stress responses, namely unfolded protein response, DNA damage response, and in aryl hydrocarbon receptor (AhR) and p53 signaling, were analyzed. This analysis revealed induction of GREM1, EGR1, CYP1A1, CDK1A, PUMA, NOXA and GDF15 and suppression of SOX9 in response to PM0.5 exposure. Analysis of eicosanoids showed no oxidative damage and only a weak anti-inflammatory response. In conclusion, this study helps to identify novel gene markers, GREM1, EGR1, GDF15 and SOX9, that may represent a valuable tool for routine testing of PM0.5-induced in vitro toxicity in lung epithelial cells.

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Section: Discussioncontrasting

confidence: 53%

“…Additionally, changes in the levels of released arachidonic acid (AA) metabolites were examined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) as they represent a functional readout of induction of oxidative stress and inflammation and/or anti-inflammatory response [29,30].…”

Section: Introductionmentioning

confidence: 99%

Screening of Cellular Stress Responses Induced by Ambient Aerosol Ultrafine Particle Fraction PM0.5 in A549 Cells

Šimečková¹,

Marvanová²,

Kulich³

et al. 2019

IJMS

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“…Líbalová et al (2014) reported strong upregulation of CYP1A1 and 1B1 gene expression upon exposure of human lung A549 cells to the extractable organic matters (EOMs) from the respirable fraction of airborne PM2.5 particles (< 2.5 µm) from three heavily polluted areas of the Czech Republic. Libalova et al (2016) demonstrated a considerable increase of CYP1A1 and 1B1 mRNA upon exposure of BEAS-2B cell line to diesel exhaust particles and Rynning et al (2018) demonstrated increases of the same CYPs mRNAs in HBEC3 (human bronchial epithelial cell line) upon exposure to diesel exhaust particles. Longhin et al (2016) observed increases in the mRNA levels of AKR1C1, 1C2 and 1C3 upon exposure of the BEAS-2B human lung cancer cell line to urban particulate matter and Libalova et al (2016) demonstrated in BEAS-2B cells a considerable increase of AKR1C2, 1C3 and 1C4 mRNA upon treatment with diesel exhaust particles.…”

Section: Some Examples Of Studies On Xenobiotica-metabolizing Enzyme mentioning

confidence: 95%

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

2019

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The xenobiotic metabolism in the lung, an organ of first entry of xenobiotics into the organism, is crucial for inhaled compounds entering this organ intentionally (e.g. drugs) and unintentionally (e.g. work place and environmental compounds). Additionally, local metabolism by enzymes preferentially or exclusively occurring in the lung is important for favorable or toxic effects of xenobiotics entering the organism also by routes other than by inhalation. The data collected in this review show that generally activities of cytochromes P450 are low in the lung of all investigated species and in vitro models. Other oxidoreductases may turn out to be more important, but are largely not investigated. Phase II enzymes are generally much higher with the exception of UGT glucuronosyltransferases which are generally very low. Insofar as data are available the xenobiotic metabolism in the lung of monkeys comes closed to that in the human lung; however, very few data are available for this comparison. Second best rate the mouse and rat lung, followed by the rabbit. Of the human in vitro model primary cells in culture, such as alveolar macrophages and alveolar type II cells as well as the A549 cell line appear quite acceptable. However, (1) this generalization represents a temporary oversimplification born from the lack of more comparable data; (2) the relative suitability of individual species/models is different for different enzymes; (3) when more data become available, the conclusions derived from these comparisons quite possibly may change.

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“…Eicosanoids, including prostaglandins, thromboxanes, and hydroxyeicosatetraenoic acids, are enzymatic oxidation products of arachidonic acid. Eicosanoids are biologically active lipid mediators with implication for inflammation and carcinogenesis 46,47 . Our data demonstrated that genes related to oxidative stress were not induced and no changes were detected in concentration levels of proinflammatory eicosanoids.…”

Section: Discussionmentioning

confidence: 99%

Gadolinium labelled nanoliposomes as the platform for MRI theranostics: in vitro safety study in liver cells and macrophages

Šimečková

Hubatka

Kotouček

et al. 2020

Sci Rep

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Gadolinium (Gd)-based contrast agents are extensively used for magnetic resonance imaging (MRi). Liposomes are potential nanocarrier-based biocompatible platforms for development of new generations of MRi diagnostics. Liposomes with Gd-complexes (Gd-lip) co-encapsulated with thrombolytic agents can serve both for imaging and treatment of various pathological states including stroke. in this study, we evaluated nanosafety of Gd-lip containing pe-DtpA chelating Gd +3 prepared by lipid film hydration method. We detected no cytotoxicity of Gd-lip in human liver cells including cancer HepG2, progenitor (non-differentiated) HepaRG, and differentiated HepaRG cells. Furthermore, no potential side effects of Gd-lip were found using a complex system including general biomarkers of toxicity, such as induction of early response genes, oxidative, heat shock and endoplasmic reticulum stress, DnA damage responses, induction of xenobiotic metabolizing enzymes, and changes in sphingolipid metabolism in differentiated HepaRG. Moreover, Gd-lip did not show pro-inflammatory effects, as assessed in an assay based on activation of inflammasome NLRP3 in a model of human macrophages, and release of eicosanoids from HepaRG cells. in conclusion, this in vitro study indicates potential in vivo safety of Gd-lip with respect to hepatotoxicity and immunopathology caused by inflammation.Gadolinium (Gd) -based contrast agents are extensively used for magnetic resonance imaging (MRI). Gd +3 forms insoluble phosphate salt in biological fluids and cultivation media. Therefore, Gd +3 is used in complexed forms of soluble chelates. These complexes are believed to be stable and non-toxic because of a high stability constant 1 . Recently, accumulation of Gd-based contrast agents has been demonstrated in various organs like kidney, liver and nervous system. It is supposed that toxic effects can be caused by dissociation of Gd ions from chelated complexes 2,3 . Case reports pointed to the induction of nephrotoxicity, hepatotoxicity and neurotoxicity and rare acute adverse reactions to Gd-based contrast agents were also observed in patients 4 .Liposomes, phospholipid-based vesicles, are widely studied as potential nanocarriers of both MRI contrast agents, including Gd +3 , and drug molecules, such as thrombolytic agents 1,5 . Therefore, liposomes can serve as diagnostic as well as theranostic agents for imaging and treatment of various pathological states and illnesses such as cancer, ischemic stroke and vasculature of different organs including liver and spleen 6,7 . Thus, liposomes represent a favourable platform for a new generation of targeted diagnostic and theranostic systems 8 .Liposomes composed of a Gd-chelating lipid, such as 1,2-distearoyl-sn-glycero-3-p hosphoethanolamine-N-diethylenetriaminepentaacetic acid (PE-DTPA (Gd)), can be easily modified to capture targeting moieties on their surface using different chemistries including copper-free click-chemistry. Moreover, different surface coating of liposomes including polyethylene glycol, hyalu...

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In Vitro Transformation of Human Bronchial Epithelial Cells by Diesel Exhaust Particles: Gene Expression Profiling and Early Toxic Responses

Cited by 23 publications

References 60 publications

Screening of Cellular Stress Responses Induced by Ambient Aerosol Ultrafine Particle Fraction PM0.5 in A549 Cells

Screening of Cellular Stress Responses Induced by Ambient Aerosol Ultrafine Particle Fraction PM0.5 in A549 Cells

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

Gadolinium labelled nanoliposomes as the platform for MRI theranostics: in vitro safety study in liver cells and macrophages

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