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.

• Klíčová slova
• AhR, NF-κB, alveolar epithelial type II cells, cytokines, inflammation, prostaglandins,
• MeSH
• buňky A549 MeSH
• látky znečišťující životní prostředí * toxicita   MeSH
• lidé MeSH
• NF-kappa B * metabolismus   MeSH
• receptory aromatických uhlovodíků * metabolismus   MeSH
• zánět * patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• látky znečišťující životní prostředí * MeSH
• NF-kappa B * MeSH
• receptory aromatických uhlovodíků * MeSH

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.

• MeSH
• diethylentriaminpentaacetát gadolinia * škodlivé účinky   toxicita   MeSH
• fibrinolytika MeSH
• fosfatidylethanolaminy * škodlivé účinky   toxicita   MeSH
• hepatocyty účinky léků   MeSH
• inflamasomy MeSH
• kontrastní látky * MeSH
• kultivované buňky MeSH
• lidé MeSH
• liposomy * MeSH
• magnetická rezonanční tomografie * MeSH
• makrofágy účinky léků   MeSH
• nanočástice MeSH
• nosiče léků * MeSH
• protein NLRP3 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• diethylentriaminpentaacetát gadolinia * MeSH
• fibrinolytika MeSH
• fosfatidylethanolaminy * MeSH
• gadolinium phosphatidylethanolamine-DTPA MeSH Prohlížeč
• inflamasomy MeSH
• kontrastní látky * MeSH
• liposomy * MeSH
• NLRP3 protein, human MeSH Prohlížeč
• nosiče léků * MeSH
• protein NLRP3 MeSH

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.

• Klíčová slova
• AhR, PM0.5, early stress response, eicosanoids, inflammation, p53, ultrafine particulate matter, unfolded protein response (UPR),
• MeSH
• aerosoly MeSH
• buňky A549 MeSH
• epitelové buňky metabolismus   patologie   MeSH
• látky znečišťující vzduch toxicita   MeSH
• lidé MeSH
• pevné částice toxicita   MeSH
• plíce metabolismus   patologie   MeSH
• regulace genové exprese účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aerosoly MeSH
• látky znečišťující vzduch MeSH
• pevné částice MeSH

OBJECTIVES: This study aimed to assess the biological impact of occupational exposure to diesel exhaust (DE) including DE particles (DEP) from heavy-duty diesel-powered equipment in Norwegian tunnel finishing workers (TFW). METHODS: TFW (n=69) and referents (n=69) were investigated for bulky DNA adducts (by 32P-postlabelling) and expression of microRNAs (miRNAs) (by small RNA sequencing) in peripheral blood mononuclear cells (PBMC), as well as circulating free arachidonic acid (AA) and eicosanoid profiles in plasma (by liquid chromatography-tandem mass spectrometry). RESULTS: PBMC from TFW showed significantly higher levels of DNA adducts compared with referents. Levels of DNA adducts were also related to smoking habits. Seventeen miRNAs were significantly deregulated in TFW. Several of these miRNAs are related to carcinogenesis, apoptosis and antioxidant effects. Analysis of putative miRNA-gene targets revealed deregulation of pathways associated with cancer, alterations in lipid molecules, steroid biosynthesis and cell cycle. Plasma profiles showed higher levels of free AA and 15-hydroxyeicosatetraenoic acid, and lower levels of prostaglandin D2 and 9-hydroxyoctadecadienoic acid in TFW compared with referents. CONCLUSION: Occupational exposure to DE/DEP is associated with biological alterations in TFW potentially affecting lung homoeostasis, carcinogenesis, inflammation status and the cardiovascular system. Of particular importance is the finding that tunnel finishing work is associated with an increased level of DNA adducts formation in PBMC.

• Klíčová slova
• biomonitoring, diesel fumes, particulates, polyaromatic hydrocarbons (pahs), toxicology,
• MeSH
• adukty DNA krev   MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• inhalační expozice analýza   MeSH
• látky znečišťující vzduch v pracovním prostředí analýza   MeSH
• leukocyty mononukleární chemie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lineární modely MeSH
• lipidy krev   MeSH
• mikro RNA krev   MeSH
• pracovní expozice škodlivé účinky   MeSH
• průřezové studie MeSH
• stavebnictví * MeSH
• výfukové emise vozidel toxicita   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Norsko MeSH
• Názvy látek
• adukty DNA MeSH
• biologické markery MeSH
• látky znečišťující vzduch v pracovním prostředí MeSH
• lipidy MeSH
• mikro RNA MeSH
• výfukové emise vozidel MeSH