title: Autophagy plays an essential role in cigarette smoke-induced expression of MUC5AC in airway epithelium.
abstract: Mucus hypersecretion is a common pathological feature of chronic airway inflammatory diseases including chronic obstructive pulmonary disease (COPD). However, the molecular basis for this condition remains incompletely understood. We have previously demonstrated a critical role of autophagy in COPD pathogenesis through mediating apoptosis of lung epithelial cells. In this study, we aimed to investigate the function of autophagy as well as its upstream and downstream signals in cigarette smoke-induced mucus production in human bronchial epithelial (HBE) cells and in mouse airways. Cigarette smoke extract (CSE), as well as the classical autophagy inducers starvation or Torin-1, significantly triggered MUC5AC expression, and inhibition of autophagy markedly attenuated CSE-induced mucus production. The CSE-induced autophagy was mediated by mitochondrial reactive oxygen species (mitoROS), which regulated mucin expression through the JNK and activator protein-1 pathway. Epidermal growth factor receptor (EGFR) was also required for CSE-induced MUC5AC in HBE cells, but it exerted inconsiderable effects on the autophagy-JNK signaling cascade. Airways of mice with dysfunctional autophagy-related genes displayed a markedly reduced number of goblet cells and attenuated levels of Muc5ac in response to cigarette smoke exposure. These results altogether suggest that mitoROS-dependent autophagy is essential for cigarette smoke-induced mucus hyperproduction in airway epithelial cells, and reemphasize autophagy inhibition as a novel therapeutic strategy for chronic airway diseases.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and.
authors.forename: Jie-Sen
authors.initials: JS
authors.lastname: Zhou
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and.
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Zhou
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and.
authors.forename: Yin-Fang
authors.initials: YF
authors.lastname: Wu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and.
authors.forename: Zhou-Yang
authors.initials: ZY
authors.lastname: Li
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and.
authors.forename: Nan-Xia
authors.initials: NX
authors.lastname: Xuan
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and.
authors.forename: Wen
authors.initials: W
authors.lastname: Hua
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and.
authors.forename: Song-Min
authors.initials: SM
authors.lastname: Ying
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and State Key Lab of Respiratory Disease, Guangzhou, China.
authors.forename: Hua-Hao
authors.initials: HH
authors.lastname: Shen
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; and zhihuachen2010@163.com.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Chen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism; D015870:Gene Expression; D020397:Goblet Cells; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D055271:Mucin 5AC / Q000235:genetics* / Q000378:metabolism; D009093:Mucus / Q000378:metabolism; D009287:Naphthyridines / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D012907:Smoking / Q000378:metabolism*; D014026:Nicotiana / Q000737:chemistry; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009287:Naphthyridines; D018808:Transcription Factor AP-1; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: autophagy; chronic obstructive pulmonary disease; cigarette smoke; epithelium; mucus