Involvement of reactive oxygen species in the metabolic pathways triggered by diesel exhaust particles in human airway epithelial cells.
Diesel exhaust particles (DEP) induce a proinflammatory response in human bronchial epithelial cells (16HBE) characterized by the release of proinflammatory cytokines after activation of transduction pathways involving MAPK and the transcription factor NF-kappaB. Because cellular effects induced by DEP are prevented by antioxidants, they could be mediated by reactive oxygen species (ROS). Using fluorescent probes, we detected ROS production in bronchial and nasal epithelial cells exposed to native DEP, organic extracts of DEP (OE-DEP), or several polyaromatic hydrocarbons. Carbon black particles mimicking the inorganic part of DEP did not increase ROS production. DEP and OE-DEP also induced the expression of genes for phase I [cytochrome P-450 1A1 (CYP1A1)] and phase II [NADPH quinone oxidoreductase-1 (NQO-1)] xenobiotic metabolization enzymes, suggesting that DEP-adsorbed organic compounds become bioavailable, activate transcription, and are metabolized since the CYP1A1 enzymatic activity is increased. Because NQO-1 gene induction is reduced by antioxidants, it could be related to the ROS generated by DEP, most likely through the activation of the stress-sensitive Nrf2 transcription factor. Indeed, DEP induced the translocation of Nrf2 to the nucleus and increased protein nuclear binding to the antioxidant responsive element. In conclusion, we show that DEP-organic compounds generate an oxidative stress, activate the Nrf2 transcription factor, and increase the expression of genes for phase I and II metabolization enzymes.
Laboratoire de Cytophysiologie et Toxicologie cellulaire, Université Paris 7 - Denis Diderot, Tour 53-54, 3e étage, case courrier 7073, 2 place Jussieu, 75251 Paris cedex 05, France. baulig@paris7.jussieu.fr
Augustin
A
Baulig
Michèle
M
Garlatti
Véronique
V
Bonvallot
Alexandre
A
Marchand
Robert
R
Barouki
Francelyne
F
Marano
Armelle
A
Baeza-Squiban
D001980:Bronchi / Q000166:cytology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D001335:Vehicle Emissions / Q000633:toxicity*
D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D001335:Vehicle Emissions; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human