The role of EGFR pathway in the pathogenesis of cigarette smoke-related airway mucus hypersecretion

Abstract

Chronic obstructive pulmonary disease (COPD) has been the fourth leading cause of death worldwide and is predicted to be the third by 2030. COPD is a progressive inflammatory disease characterized by irreversible limitation of airflow. There are several major pathogenic mechanisms, including oxidative stress, chronic inflammation, accelerated lung ageing, and protease-antiprotease imbalance. In this investigation, I focused on the most important risk factor of COPD – cigarette smoking. It was estimated that approximately half of the COPD cases were attributed to cigarette smoking. Chronic exposure of airway to cigarette smokes (CS) has been found to promote excessive mucus production and amplify inflammatory response leading to impaired mucociliary function and ultimately airway obstruction. Previous researchers used a selective epidermal growth factor receptor (EGFR) inhibitor, AG1478, to confirm that the EGFR pathway played a crucial role in airway goblet cell hyperplasia, mucus hypersecretion, and inflammation. The effect of cigarette smoke medium (CSM) on various secreted mucins mRNA expression and inflammatory cytokine interleukin (IL)-8 release was examined in this study. I looked at the effect of AG1478 pretreatment on the regulation of CSM-induced mucins mRNA expression and IL-8 release in vitro using NCI-H292 airway epithelial cells. Finally, I elucidated whether CSM-induced elevation of mucins mRNA and IL-8 release would be via phosphorylation of EGFR using selective EGFR tyrosine kinase inhibitor AG1478. Recent data demonstrated that CSM caused a concentration-dependent elevation of MUC5AC and MUC5B mRNA and IL-8 release in NCI-H292 cells, but no significant induction of MUC2 mRNA was observed. AG1478 alone had no effect on mucins mRNA level and IL-8 release but inhibited CSM-induced elevation of MUC5AC and MUC5B mRNA and IL-8 release. Phosphorylation of EGFR was confirmed to be crucial in the CS-induction of mucins mRNA and IL-8 release. Lastly, immunohistochemistry was used to show that AG1478 effectively inhibited CSM-induced MUC5AC and MUC5B protein expression. Taken together, the current findings suggest that EGFR activation by phosphorylation is crucial in CSM-induced mucus hypersecretion and airway inflammation. Moreover, recent results suggest that AG1478 may be a possible pharmacological intervention for the symptomatic treatment of mucus hypersecretion. It may also possess anti-inflammatory property to downregulate the release of IL-8. However, further investigations are needed to confirm the therapeutic effect of AG1478 in vivo.