Rapid Communication Fine Particulate Matter Induces Amphiregulin Secretion by Bronchial Epithelial Cells

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 m (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–colonystimulating factor (GM-CSF) release and a neutralizing antiEGFR 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. Exposure to particulate matter (PM) is associated with increased morbidity and mortality for respiratory and cardiovascular disorders (1, 2). Controlled human exposure has revealed that one of the most striking effects of PM exposure is inflammation of the pulmonary airways (3). Furthermore, recent studies highlight how long-term exposure to PM can promote airway remodeling in small airways (4). A study of people living in Mexico City, notorious for its