Epidermal Growth Factor Receptor Inhibitor Ag1478 Inhibits Mucus Hypersecretion in Airway Epithelium

Abstract

Background Mucus hypersecretion and neutrophil infiltration are important characteristics of airway inflammation. Epidermal growth factor receptor (EGFR) transactivation induces mucus and inflammatory cytokine secretion from airway epithelial cells. To elucidate the roles of EGFR in airway inflammation, the in vitro effects on mucin production and interleukin (IL) 8 secretion from cultured airway epithelial cells and the in vivo effects on mucus hypersecretion and neutrophil infiltration in rat nasal mucosa of the EGFR tyrosine kinase inhibitor AG1478 were examined. Methods The in vitro effects of AG1478 treatment of cultured NCI-H292 cells on lipopolysaccharide (LPS) induced or tumor necrosis factor (TNF) a induced MUC5AC mucin and IL-8 secretion were evaluated. Hypertrophic and metaplastic changes of goblet cells, mucus production and neutrophil infiltration in rat nasal epithelium were induced by intranasal instillation of LPS in vivo, and the inhibitory effects of AG1478 by intraperitoneal injection or intranasal instillation were examined. Results AG1478 (1-1000 nM) significantly inhibited both LPS-induced and TNF-α-induced secretion of MUC5AC and IL-8 from cultured NCI-H292 cells in a dose-dependent manner. The expression of MUC5AC and IL-8 messenger RNAs was also significantly inhibited. Intranasal instillation of AG1478 one hour after intranasal LPS instillation significantly inhibited LPS-induced goblet cell metaplasia, mucus production, and neutrophil infiltration in rat nasal epithelium, as did intraperitoneal injection of AG1478 one hour before LPS instillation. Conclusions These results indicated that EGFR transactivation plays an important role in mucin and IL-8 secretion from airway epithelial cells. Intranasal instillation of an EGFR tyrosine kinase inhibitor may be a new therapeutic approach for the treatment of upper airway inflammation.