title: Autophagy is essential for ultrafine particle-induced inflammation and mucus hyperproduction in airway epithelium.
abstract: Environmental ultrafine particulate matter (PM) is capable of inducing airway injury, while the detailed molecular mechanisms remain largely unclear. Here, we demonstrate pivotal roles of autophagy in regulation of inflammation and mucus hyperproduction induced by PM containing environmentally persistent free radicals in human bronchial epithelial (HBE) cells and in mouse airways. PM was endocytosed by HBE cells and simultaneously triggered autophagosomes, which then engulfed the invading particles to form amphisomes and subsequent autolysosomes. Genetic blockage of autophagy markedly reduced PM-induced expression of inflammatory cytokines, e.g. IL8 and IL6, and MUC5AC in HBE cells. Mice with impaired autophagy due to knockdown of autophagy-related gene Becn1 or Lc3b displayed significantly reduced airway inflammation and mucus hyperproduction in response to PM exposure in vivo. Interference of the autophagic flux by lysosomal inhibition resulted in accumulated autophagosomes/amphisomes, and intriguingly, this process significantly aggravated the IL8 production through NFKB1, and markedly attenuated MUC5AC expression via activator protein 1. These data indicate that autophagy is required for PM-induced airway epithelial injury, and that inhibition of autophagy exerts therapeutic benefits for PM-induced airway inflammation and mucus hyperproduction, although they are differentially orchestrated by the autophagic flux.
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Yin-Fang
authors.initials: YF
authors.lastname: Wu
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Ping-Li
authors.initials: PL
authors.lastname: Wang
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Wu
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Zhou-Yang
authors.initials: ZY
authors.lastname: Li
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Jie-Sen
authors.initials: JS
authors.lastname: Zhou
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Chao
authors.initials: C
authors.lastname: Cao
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Mao
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: b Core Facilities, Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Wang
authors.affiliation: c Department of Pediatrics , University of Tennessee Health Science Center, Children's Foundation Research Institute , Memphis , TN , USA.
authors.forename: Stephania A
authors.initials: SA
authors.lastname: Cormier
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Song-Min
authors.initials: SM
authors.lastname: Ying
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital Zhejiang University School of Medicine , Hangzhou , Zhejiang.|d State Key Lab of Respiratory Disease, National Clinical Research Center for Respiratory Disease , Guangzhou , China.
authors.forename: Hua-Hao
authors.initials: HH
authors.lastname: Shen
mesh_terms: D000818:Animals; D001343:Autophagy; D000071186:Beclin-1 / Q000378:metabolism; D001980:Bronchi / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004705:Endocytosis; D004847:Epithelial Cells / Q000473:pathology / Q000648:ultrastructure; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D009093:Mucus / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010316:Particle Size; D052638:Particulate Matter / Q000009:adverse effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000071186:Beclin-1; C115010:Becn1 protein, mouse; D016207:Cytokines; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D052638:Particulate Matter; D018808:Transcription Factor AP-1
keywords: airway inflammation; autophagy; endocytosis; mucus hyperproduction; ultrafine particulate matter