Obstructive Lung Diseases: COPD: Etiology |

Autophagy Plays an Essential Role in Cigarette Smoke-Induced Mucin Expression in Airway Epithelium FREE TO VIEW

Huahao Shen; Jie Zhou; Yin Wu; Yun Zhao; Yong Wang; Hongbin Zhou; Zhou Li; Nanxia Xuan; Songmin Ying; Wen Li; Zhihua Chen
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Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

Copyright 2016, American College of Chest Physicians. All Rights Reserved.

Chest. 2016;149(4_S):A359. doi:10.1016/j.chest.2016.02.374
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SESSION TYPE: Original Investigation Poster

PRESENTED ON: Saturday, April 16, 2016 at 11:45 AM - 12:45 PM

PURPOSE: Mucus hypersecretion is a common pathological feature of chronic airway inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Despite numerous studies before, the molecular bases for this condition are still not clear. We have recently demonstrated that cigarette smoking induced autophagy in airway epithelial cells which eventually contributed to the epithelial cell apoptosis and the development of emphysema. In this study, we investigated the relationship between autophagy and mucus expression in context of cigarette smoking-induced airway inflammation.

METHODS: Human bronchial epithelial cell lines (HBECs) were stimulated with 3% CS extract (CSE) for 24h. Autophagy inducer starvation and inhibitors, Bafilomycin A1 (BafA1, 10 nM) and Chloroquine (CQ, 10 mM), siRNAs for Atg5, Atg12, LC3B were employed to change the level of autophagyin HBE cells. AP-1 inhibitor sp600125, MitoROS specific inhibitor MitoTEMP, and siRNAs for c-Jun and GRP78 were used to address their specific roles of these pathways in smoking induced autophagy and mucus production. Mice were instilled with CSE intratracheally to mimic a smoking-induced mucus hypersecretion model. Muc5ac expression was measured by real-time PCR and immunofluorescence. LC3B, c-Fos, c-Jun, GRP78 expression were determined by Western blotting.

RESULTS: Classical autophagy stimulant starvation could induce Muc5ac gene expression in HBECs. Silencing of autophagy related gene, Atg5, Atg12 and LC3B, or biochemical inhibition of autophagy by BafA1 or CQ, significantly protected CSE induced Muc5ac expression. Mitochondrial specific ROS and ER stress were induced by CSE, and both these pathways appeared to partially mediate CSE-induced autophagy and subsequent mucus production. Moreover, autophagy regulated the CSE-induced activation of AP-1, and inhibition of AP-1 by sp600125 or c-Jun siRNA notably attenuated CSE-induced Muc5ac expression. In vivo, LC3B-/- mice displayed a marked decrease of mucus expression in response to CSE instillation.

CONCLUSIONS: We demonstrate that autophagy positively regulates CSE-induced Muc5ac expression by activating AP-1, and this process is orchestrated by upstream signals such as Mito-ROS and ER stress.

CLINICAL IMPLICATIONS: Our research provides new molecular mechanism and suggests new therapeutic target for mucus hyperproduction in chronic airway diseases.

DISCLOSURE: The following authors have nothing to disclose: Huahao Shen, Jie Zhou, Yin Wu, Yun Zhao, Yong Wang, Hongbin Zhou, Zhou Li, Nanxia Xuan, Songmin Ying, Wen Li, Zhihua Chen

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