Particulate pollution is suspected to contribute to obstructive lung diseases characterized by chronic inflammation, mucus hypersecretion and bronchial remodeling. Our aim was to study the effect of real-world particulate matter (PM) on the expression of a mucin, MUC5AC, focusing on the role of the epidermal growth factor receptor (EGFR) pathway. MUC5AC induction was studied in vivo in mice trachea and in vitro in human bronchial epithelial cells (HBEC) exposed to urban fine PM. Fine PM were able to induce MUC5AC mRNA in mice trachea after 48 h of exposure (50 μg PM/mouse), and MUC5AC mRNA and protein in HBEC after 24 h of exposure (from 5 μg PM/cm(2)). It was associated with the increased expression of amphiregulin (AREG), an EGFR ligand. Experiments with conditioned media (media from PM-treated cells) demonstrated the involvement of AREG on MUC5AC induction as MUC5AC induction by media from PM-treated cells was prevented in the presence of either EGFR- or AREG-neutralizing antibodies. The effect of an inhibitor of a metalloprotease involved in the AREG shedding confirmed the autocrine loop made by AREG leading to MUC5AC induction by fine PM. We also demonstrated that IL-8 pro-inflammatory cytokine induction was dependent on the same autocrine mechanisms. We demonstrate for the first time that MUC5AC expression and production is increased by short-term exposure to fine PM through an autocrine effect of AREG. Our study provides mechanistic explanations to the exacerbation of obstructive lung diseases induced by particulate pollution characterized by mucus hypersecretion and chronic inflammation.
Exposure to titanium dioxide (TiO2) nanoparticles (NPs) is associated with lung remodeling, but the underlying mechanisms are unknown. Matrix metalloprotease (MMP)-1 is an important actor in matrix homeostasis and could therefore participate in TiO2 NP effects. Our aim was to evaluate the effects of TiO2 NPs on MMP-1 expression and activity in lung pulmonary fibroblasts and to understand the underlying mechanisms and assess the importance of the physicochemical characteristics of the particles in these effects. Human pulmonary fibroblasts (MRC-5 cell line and primary cells) were exposed to 10 or 100 μg/cm(2) TiO2 (two anatases, two anatase/rutile mix, one rutile NP, and one micrometric) and carbon black (CB) NPs for 6 to 48 hours. We examined cell viability, MMP-1 expression and activity, and the implication of oxidative stress, transforming growth factor (TGF)-β, extracellular MMP inducer, and IL-1β in MMP-1 expression. All TiO2 NPs induced MMP-1 (mRNA and protein expression), repression of procollagen-1, and α-actin expression, but only the two anatase/rutile mix induced MMP-1 activity. Micrometric TiO2 had smaller effects than TiO2 NPs, and CB NPs did not induce MMP-1. MMP-1 induction by TiO2 NPs was not related to TGF-β, oxidative stress, or EMPRIN expression but was related to IL-1β expression, which partly drives MMP-1 induction by two TiO2 NPs (one anatase/rutile mix and the rutile one). Taken together, our results show that TiO2 NPs are potent inducers and regulators of MMP-1 expression and activity, partly via an IL-1β-dependent mechanism. This may explain TiO2 lung remodeling effects.
Several studies suggest that the biological responses induced by manufactured nanoparticles (MNPs) may be linked to their accumulation within cells. However, MNP internalisation has not yet been sufficiently characterised. Therefore, the aim of this study was to compare the intracellular uptake of three different MNPs: two made of carbon black (CB) and one made of titanium dioxide (TiO(2)), in 16HBE bronchial epithelial cells and MRC5 fibroblasts. Transmission electron microscopy was used to evaluate the intracellular accumulation. Different parameters were analysed following a time and dose-relationship: localisation of MNPs in cells, percentage of cells having accumulated MNPs, number of aggregated MNPs in cells, and the size of MNP aggregates in cells. The results showed that MNPs were widely and rapidly accumulated in 16HBE cells and MRC5 fibroblasts. Moreover, MNPs accumulated chiefly as aggregates in cytosolic vesicles and were absent from the mitochondria or nuclei. CB and TiO(2) MNPs had similar accumulation patterns. However, TiO(2) aggregates had a higher size than CB aggregates. Intracellular MNP accumulation was dissociated from cytotoxicity. These results suggest that cellular uptake of MNPs is a common phenomenon occurring in various cell types.
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