title: Cigarette smoke induces mucin hypersecretion and inflammatory response through the p66shc adaptor protein-mediated mechanism in human bronchial epithelial cells.
abstract: The p66Shc adaptor protein is a newly recognized mediator of mitochondrial dysfunction and might play a role in cigarette smoke (CS)-induced airway epithelial cell injury. CS can induce an excessive amount of reactive oxygen species (ROS) generation, which can cause mitochondrial depolarization and injury through the oxidative stress-mediated Serine36 phosphorylation of p66Shc. The excessive production of ROS can trigger an inflammatory response and mucin hypersecretion by enhancing the transcriptional activity of pro-inflammatory cytokines and mucin genes. Therefore, we speculate that p66Shc plays an essential role in airway epithelial cell injury and the process of mucin generation in CS-induced chronic inflammatory airway diseases. Our present study focuses on the role of p66Shc in ROS generation, and on the resulting mitochondrial dysfunction, inflammatory response and mucus hypersecretion in CS-stimulated human bronchial epithelial cells (16HBE). We found that CS disturbed the mitochondrial function by increasing the level of phosphorylated p66Shc in these cells and that the effects were significantly reduced by silencing p66Shc. Conversely, the ectopic overexpression of wild-type p66Shc enhanced these effects. We also found that high levels of ROS inhibited FOXO3a transcriptional activity, which led to NF-κB activation. Subsequently, activated NF-κB promoted pro-inflammatory cytokine production and mucin hypersecretion. Thus, manipulating p66Shc might offer a new therapeutic modality with which to treat chronic inflammatory airway diseases.
authors.affiliation: Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Geriatrics Medicine, First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: H M
authors.initials: HM
authors.lastname: Yu
authors.affiliation: Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; Division of Respiratory Medicine, Affiliated Hospital of Hainan Medical University, Haikou, China. Electronic address: zxd999@263.net.
authors.forename: X D
authors.initials: XD
authors.lastname: Zhou
authors.affiliation: Division of Respiratory Medicine, Affiliated Hospital of Hainan Medical University, Haikou, China.
authors.forename: H P
authors.initials: HP
authors.lastname: Huang
authors.affiliation: Division of Respiratory Medicine, Affiliated Hospital of Hainan Medical University, Haikou, China.
authors.forename: Zh
authors.initials: Zh
authors.lastname: Han
authors.affiliation: Far Eastern Scientific Center of Physiology and Pathology of Respiration, Siberian Branch, Russian Academy of Medical Sciences, Russian Federation.
authors.forename: V P
authors.initials: VP
authors.lastname: Kolosov
authors.affiliation: Far Eastern Scientific Center of Physiology and Pathology of Respiration, Siberian Branch, Russian Academy of Medical Sciences, Russian Federation.
authors.forename: J M
authors.initials: JM
authors.lastname: Perelman
mesh_terms: D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009077:Mucins / Q000096:biosynthesis*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000187:drug effects*; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014026:Nicotiana / Q000009:adverse effects*; D014162:Transfection
chemical_list: D009077:Mucins; D017382:Reactive Oxygen Species; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D012906:Smoke; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
keywords: Inflammation; MUC5AC; Mitochondria; NF-κB; ROS; p66Shc