PM2.5 Upregulates the Expression of MUC5AC via the EGFR-PI3K Pathway in Human Sinonasal Epithelial Cells.

BACKGROUND

Fine particulate matter (PM) (PM with an aerodynamic diameter <2.5 μm, PM2.5) exposure contributes to respiratory disease development and exacerbation.

OBJECTIVE

We sought to investigate the effect of PM2.5 exposure on mucociliary function in primary human nasal epithelial cells (HNECs) and the underlying mechanism.

METHODS

HNECs derived from control subjects and patients with chronic rhinosinusitis with nasal polyps were established as air-liquid interface cultures. Confluent cultures were exposed to 100 or 200 μg/mL PM2.5 for 24 h and assessed for expression of specific mucociliary-associated factors, the percentage of β-tubulin IV-positive and MUC5AC-positive cells, expression of epidermal growth factor receptor (EGFR) ligand and activation of phosphoinositide 3-kinase (PI3K)-AKT/ERK. In addition, cultures pretreated for 30 min with AG1478 (an EGFR inhibitor) or LY294002 (a PI3K inhibitor) following PM2.5 exposure were assessed for MUC5AC mRNA and protein expression.

RESULTS

PM2.5 exposure at 100 or 200 μg/mL for 24 h did not affect geminin coiled-coil domain containing, multiciliate differentiation and DNA synthesis associated cell cycle protein, FOXJ1, or DNAI2 mRNA expression or the percentage of β-tubulin IV-positive cells. However, 200 μg/mL PM2.5 exposure significantly increased mRNA expression of SAM-pointed domain-containing ETS transcription factor and MUC5AC and the percentage of MUC5AC-positive cells. PM2.5 also increased expression of EGFR ligands, including heparin-binding EGF-like growth factor and amphiregulin. Furthermore, PM2.5induced activation of PI3K, AKT, and ERK, and pretreatment of HNECs with AG1478 or LY294002 attenuated PM2.5-induced MUC5AC mRNA and protein expression.

CONCLUSIONS AND CLINICAL RELEVANCE: This study demonstrates that short-term PM2.5 exposure increases MUC5AC expression in HNECs. Furthermore, this study shows that PM2.5-induced MUC5AC expression is likely mediated through the EGFR-PI3K pathway.