Glycopyrronium bromide regulates cigarette smoke-induced epithelial mesenchymal transition by mediating ACh production

Abstract

Epithelial–mesenchymal transition (EMT) is one of the pathological features of chronic obstructive pulmonary disease (COPD) and lung cancer. Cigarette smoke (CS) stimulates the production of many factors including acetylcholine (ACh), leading to the progression of EMT in the lung. Our previous studies have shown the potential effects of glycopyrronium bromide (GB), a selective M3 receptor antagonist, on reducing acute lung inflammation induced by CS in mice. Here, we investigated the regulation of GB on CS-induced ACh production and EMT progression in a mouse model, where we found that inhalation of GB (600 µg/mL) significantly suppressed the ACh upregulation and reversed the changes of EMT-related indicators in the lung. In addition, GB prevented the EMT induced by ACh analogue methacholine (MCh) in vitro. We further explored the underlying mechanism, where we found that CS extract (CSE) and MCh exposure resulted in Akt phosphorylation, which were suppressed by GB. Moreover, the CSE or MCh exposure-induced EMT progression were restrained by Akt knockdown or inhibition. Thus, our results indicated that GB can be a potential, readily usable drug for the EMT-related diseases. Additionally, synergistic use of GB in clinics to strengthen the anti-tumor effects may provide novel therapeutic strategies for lung cancer patients with COPD.