Latest Publications

@article{vazquez-gomez_aryl_2022,

title = {Aryl Hydrocarbon Receptor (AhR) Limits the Inflammatory Responses in Human Lung Adenocarcinoma A549 Cells via Interference with NF-κB Signaling.},

author = {Gerardo Vázquez-Gómez and Martina Karasová and Zuzana Tylichová and Markéta Kabátková and Aleš Hampl and Jason Matthews and Jiří Neča and Miroslav Ciganek and Miroslav Machala and Jan Vondráček},

doi = {10.3390/cells11040707},

issn = {2073-4409},

year  = {2022},

date = {2022-02-01},

journal = {Cells},

volume = {11},

number = {4},

abstract = {Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention.},

note = {Place: Switzerland},

keywords = {*Environmental Pollutants/toxicity, *Inflammation/pathology, *NF-kappa B/metabolism, *Receptors, A549 Cells, AhR, alveolar epithelial type II cells, Aryl Hydrocarbon/metabolism, cytokines, Humans, Inflammation, NF-κB, prostaglandins},

pubstate = {published},

tppubtype = {article}

}

@article{prochazkova_adaptive_2018,

title = {Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands.},

author = {Jiřina Procházková and Simona Strapáčová and Lucie Svržková and Zdeněk Andrysík and Martina Hýžďalová and Eva Hrubá and Kateřina Pěnčíková and Helena Líbalová and Jan Topinka and Jiří Kléma and Joaquín M. Espinosa and Jan Vondráček and Miroslav Machala},

doi = {10.1016/j.toxlet.2018.04.024},

issn = {1879-3169 0378-4274},

year  = {2018},

date = {2018-08-01},

journal = {Toxicology letters},

volume = {292},

pages = {162–174},

abstract = {Exposure to persistent ligands of aryl hydrocarbon receptor (AhR) has been found to cause lung cancer in experimental animals, and lung adenocarcinomas are often associated with enhanced AhR expression and aberrant AhR activation. In order to better understand the action of toxic AhR ligands in lung epithelial cells, we performed global gene expression profiling and analyze TCDD-induced changes in A549 transcriptome, both sensitive and non-sensitive to CH223191 co-treatment. Comparison of our data with results from previously reported microarray and ChIP-seq experiments enabled us to identify candidate genes, which expression status reflects exposure of lung cancer cells to TCDD, and to predict processes, pathways (e.g. ER stress, Wnt/β-cat, IFNɣ, EGFR/Erbb1), putative TFs (e.g. STAT, AP1, E2F1, TCF4), which may be implicated in adaptive response of lung cells to TCDD-induced AhR activation. Importantly, TCDD-like expression fingerprint of selected genes was observed also in A549 cells exposed acutely to both toxic (benzo[a]pyrene, benzo[k]fluoranthene) and endogenous AhR ligands (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester and 6-formylindolo[3,2-b]carbazole). Overall, our results suggest novel cellular candidates, which could help to improve monitoring of AhR-dependent transcriptional activity during acute exposure of lung cells to distinct types of environmental pollutants.},

note = {Place: Netherlands},

keywords = {A549 Cells, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*agonists/metabolism, Azo Compounds/toxicity, Basic Helix-Loop-Helix Transcription Factors/*agonists/metabolism, Benzo(a)pyrene/toxicity, Carbazoles/toxicity, Dioxins, Environmental Pollutants/*toxicity, Fluorenes/toxicity, Gene Expression Profiling/methods, Gene Expression Regulation, Gene Regulatory Networks/drug effects, Genetic/drug effects, Global gene expression profiling, Humans, Indoles/toxicity, Ligands, Lung cancer, Lung Neoplasms/*genetics/metabolism, Neoplastic/*drug effects, Oligonucleotide Array Sequence Analysis, Polychlorinated Dibenzodioxins/toxicity, Pyrazoles/toxicity, Receptors, Signal Transduction/drug effects, Thiazoles/toxicity, Time Factors, Transcription, Transcriptional Activation/drug effects, Transcriptome/*drug effects},

pubstate = {published},

tppubtype = {article}

}

@article{strapacova_relative_2018,

title = {Relative effective potencies of dioxin-like compounds in rodent and human lung cell models.},

author = {Simona Strapáčová and Petra Brenerová and Pavel Krčmář and Patrik Andersson and Karin I. Ede and Majorie B. M. Duursen and Martin Berg and Jan Vondráček and Miroslav Machala},

doi = {10.1016/j.tox.2018.05.004},

issn = {1879-3185 0300-483X},

year  = {2018},

date = {2018-07-01},

journal = {Toxicology},

volume = {404-405},

pages = {33–41},

abstract = {Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the inducibility of AhR in the lungs, a major target of DLCs, remains poorly characterized. In this study, we developed relative effective potencies (REPs) for a series of DLCs in both rodent (MLE-12, RLE-6TN) and human (A549, BEAS-2B) lung and bronchial epithelial cell models, using expression of both canonical (CYP1A1, CYP1B1) and less well characterized (TIPARP, AHRR, ALDH3A1) AhR target genes. The use of rat, murine and human cell lines allowed us to determine both species-specific differences in sensitivity of responses to DLCs in lung cellular models and deviations from established WHO toxic equivalency factor values (TEF) values. Finally, expression of selected AhR target genes was determined in vivo, using lung tissues of female rats exposed to a single oral dose of DLCs and compared with the obtained in vitro data. All cell models were highly sensitive to DLCs, with murine MLE-12 cells being the most sensitive and human A549 cells being the least sensitive. Interestingly, we observed that four AhR target genes were more sensitive than CYP1A1 in lung cell models (CYP1B1, AHRR, TIPARP and/or ALDH3A1). We found some deviations, with strikingly low REPs for polychlorinated biphenyls PCBs 105, 167, 169 and 189 in rat RLE-6TN cells-derived REPs for a series of 20 DLCs evaluated in this study, as compared with WHO TEF values. For other DLCs, including PCBs 126, 118 and 156, REPs were generally in good accordance with WHO TEF values. This conclusion was supported by in vivo data obtained in rat lung tissue. However, we found that human lung REPs for 2,3,4,7,8-pentachlorodibenzofuran and PCB 126 were much lower than the respective rat lung REPs. Furthermore, PCBs 118 and 156 were almost inactive in these human cells. Our observations may have consequences for risk assessment. Given the differences observed between rat and human data sets, development of human-specific REP/TEFs, and the use of CYP1B1, AHRR, TIPARP and/or ALDH3A1 mRNA inducibility as sensitive endpoints, are recommended for assessment of relative effective potencies of DLCs.},

note = {Place: Ireland},

keywords = {A549 Cells, Acute/methods, AhR, Animals, Dioxin-like compounds, Dioxins/*toxicity, Dose-Response Relationship, Drug, Endogenous target genes, Female, Humans, Lung epithelial cells, Lung/*drug effects/metabolism/*pathology, Mice, Rats, Relative effective potencies, Rodentia, Species Specificity, Sprague-Dawley, Toxicity Tests},

pubstate = {published},

tppubtype = {article}

}

@article{libalova_analysis_2014,

title = {Analysis of gene expression changes in A549 cells induced by organic compounds from respirable air particles.},

author = {Helena Líbalová and Simona Krčková and Kateřina Uhlířová and Jiří Kléma and Miroslav Ciganek and Pavel Jr Rössner and Radim J. Šrám and Jan Vondráček and Miroslav Machala and Jan Topinka},

doi = {10.1016/j.mrfmmm.2014.10.002},

issn = {1873-135X 0027-5107},

year  = {2014},

date = {2014-12-01},

journal = {Mutation research},

volume = {770},

pages = {94–105},

abstract = {A number of toxic effects of respirable ambient air particles (genotoxic effects, inflammation, oxidative damage) have been attributed to organic compounds bound onto the particle surface. In this study, we analyzed global gene expression changes caused by the extractable organic matters (EOMs) from respirable airborne particles <2.5μm (PM2.5), collected at 3 localities from heavily polluted areas of the Czech Republic and a control locality with low pollution levels, in human lung epithelial A549 cells. Although the sampled localities differed in both extent and sources of air pollution, EOMs did not induce substantially different gene expression profiles. The number of transcripts deregulated in A549 cells treated with the lowest EOM concentration (10μg/ml) ranged from 65 to 85 in 4 sampling localities compared to the number of transcripts deregulated after 30μg/ml and 60μg/ml of EOMs, which ranged from 90 to 109, and from 149 to 452, respectively. We found numerous commonly deregulated genes and pathways related to activation of the aryl hydrocarbon receptor (AhR) and metabolism of xenobiotics and endogenous compounds. We further identified deregulation of expression of the genes involved in pro-inflammatory processes, oxidative stress response and in cancer and developmental pathways, such as TGF-β and Wnt signaling pathways. No cell cycle arrest, DNA repair or pro-apoptotic responses were identified at the transcriptional level after the treatment of A549 cells with EOMs. In conclusion, numerous processes and pathways deregulated in response to EOMs suggest a significant role of activated AhR. Interestingly, we did not observe substantial gene expression changes related to DNA damage response, possibly due to the antagonistic effect of non-genotoxic EOM components. Moreover, a comparison of EOM effects with other available data on modulation of global gene expression suggests possible overlap among the effects of PM2.5, EOMs and various types of AhR agonists.},

note = {Place: Netherlands},

keywords = {A549 Cells, Adenocarcinoma of Lung, Adenocarcinoma/genetics/pathology, Ah receptor, Cultured, gene expression profile, Gene Expression Profiling, Gene Expression Regulation, Gene Expression/*drug effects, Humans, Lung Neoplasms/genetics/pathology, Microarray Analysis, Neoplastic/drug effects, Organic Chemicals/*pharmacology, PAHs, Particulate Matter/*pharmacology, PM2.5, Respiratory Mucosa/drug effects/metabolism, Signal Transduction/drug effects/genetics, Tumor Cells},

pubstate = {published},

tppubtype = {article}

}