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Fine Particulate Matter Induces Amphiregulin Secretion by Bronchial Epithelial Cells

Laboratoire de Cytophysiologie et Toxicologie Cellulaire, Université Paris 7-Denis Diderot, Paris, France

Address correspondence to: Armelle Baeza-Squiban, Laboratoire de Cytophysiologie et Toxicologie Cellulaire, Université Paris 7-Denis Diderot, 2 place Jussieu, Tour 53-54, 3^e etage, case courrier 7073, 75251 Paris cedex 05, France. E-mail: baeza{at}paris7.jussieu.fr

Particulate matter (PM) is thought to be responsible for respiratory health problems. Epithelial cells exposed to particles release pro-inflammatory cytokines leading to inflammation of airways. However, the signaling cascades triggered by particles are poorly understood. We demonstrate that PM with an aerodynamic diameter < 2.5 µm (PM2.5) or diesel exhaust particles upregulate the expression of amphiregulin (AR), a ligand of the epidermal growth factor receptor (EGFR), in human bronchial epithelial cells. AR secretion was blocked by an inhibitor of the EGFR tyrosine kinase (AG1478), or a selective mitogen-activated protein (MAP) kinase/extracellular regulated kinase (Erk) inhibitor (PD98059), but not by the p38 MAP kinase inhibitor (SB203580). Thus, AR secretion is mediated through the activation of the EGFR and Erk MAP kinase pathway. In addition, AR secretion was inhibited by the antioxidant N-acetyl cysteine, but not by a neutralizing anti-EGFR, suggesting an EGFR transactivation via oxidative stress. AR may be involved in cytokine secretion, as AR can induce granulocyte macrophage–colony-stimulating factor (GM-CSF) release and a neutralizing anti-EGFR reduces the particle-induced GM-CSF release. This study indicates that PM2.5 induces the expression and secretion of AR, an EGFR ligand contributing to GM-CSF release, which may reflect an important mechanism for sustaining the proinflammatory response.

Abbreviations: amphiregulin, AR • betacellulin, BTC • carbon black, CB • diesel exhaust particles, DEP • dipalmitoyl lecithin, DPL • epidermal growth factor, EGF • EGF receptor, EGFR • extracellular regulated kinase, Erk • human bronchial epithelial cells, HBE cells • heparin-binding EGF, HB-EGF • interleukin-8, IL-8 • mitogen-activated protein, MAP • mitogen-activated protein kinase/Erk kinase, MEK • N-acetyl cysteine, NAC • particulate matter with an aerodynamic diameter < 2.5µm, PM2.5 • reactive oxygen species, ROS • transforming growth factor-, TGF- • Ultroser G, UG

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