title: Cigarette smoke-mediated oxidative stress induces apoptosis via the MAPKs/STAT1 pathway in mouse lung fibroblasts.
abstract: Cigarette smoking is the major aetiologic factor in chronic obstructive pulmonary disease (COPD). Lung fibroblasts are key participants in the maintenance of the extracellular matrix within the lung parenchyma. However, it still remains unknown how pulmonary fibroblasts are affected by cigarette smoking. Therefore, in this study, we isolated lung fibroblasts from mice and determined the apoptotic mechanism in response to cigarette smoke extract (CSE). When the lung fibroblasts were exposed to CSE, the generation of ROS was increased as shown by H2-DCFDA staining and Flow Cytometry. By immunocytochemistry, Ki67 expressing cells gradually decreased in a dose-dependent manner. The nitrite concentration in the supernatants increased, while the SOD activity and GSH recycling decreased in response to CSE. CSE increased the mRNA levels of TNF-α and COX-2, and the secretory proteins TNF-α and IL-6 increased as measured by ELISA. We next determined whether this inflammatory process is associated with the Bax/Bcl-2 apoptosis pathway. The Bax/Bcl-2 mRNA ratio increased, and cleaved caspase-3 protein was activated in the lung fibroblasts treated with CSE. Moreover, CSE induced the phosphorylation of STAT1 at Tyr701/Ser727 and increased the activation of ERK1/2, p38, and JNK in the MAPK pathway. Taken together, these data suggest that CSE-mediated inflammation alters the redox regulation via the MAPK-STAT1 pathway, leading to intrinsic apoptosis of lung fibroblasts.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, Gangwon 200-701, Republic of Korea.
authors.forename: Hanbyeol
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, Gangwon 200-701, Republic of Korea.
authors.forename: Jeong-Ran
authors.initials: JR
authors.lastname: Park
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, Gangwon 200-701, Republic of Korea.
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Kangwon National University, Chuncheon, Gangwon 200-701, Republic of Korea.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Kangwon National University, Chuncheon, Gangwon 200-701, Republic of Korea.
authors.forename: Seok-Ho
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, Gangwon 200-701, Republic of Korea.
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Park
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, Gangwon 200-701, Republic of Korea. Electronic address: seran@knagwon.ac.kr.
authors.forename: Se-Ran
authors.initials: SR
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D015850:Interleukin-6; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D009569:Nitric Oxide; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D005978:Glutathione
keywords: Apoptosis; Cigarette smoke extract; Lung fibroblast; MAPKs; STAT1