title: The c-Jun N-terminal kinase signaling pathway mediates chrysotile asbestos-induced alveolar epithelial cell apoptosis.
abstract: Exposure to chrysotile asbestos exposure is associated with an increased risk of mortality in combination with pulmonary diseases including lung cancer, mesothelioma and asbestosis. Multiple mechanisms by which chrysotile asbestos fibers induce pulmonary disease have been identified, however the role of apoptosis in human lung alveolar epithelial cells (AEC) has not yet been fully explored. Accumulating evidence implicates AEC apoptosis as a crucial event in the development of both idiopathic pulmonary fibrosis and asbestosis. The aim of the present study was to determine whether chrysotile asbestos induces mitochondria‑regulated (intrinsic) AEC apoptosis and, if so, whether this induction occurs via the activation of mitogen‑activated protein kinases (MAPK). Human A549 bronchoalveolar carcinoma‑derived cells with alveolar epithelial type II‑like features were used. The present study showed that chrysotile asbestos induced a dose‑ and time‑dependent decrease in A549 cell viability, which was accompanied by the activation of the MAPK c‑Jun N‑terminal kinases (JNK), but not the MAPKs extracellular signal‑regulated kinase 1/2 and p38. Chrysotile asbestos was also shown to induce intrinsic AEC apoptosis, as evidenced by the upregulation of the pro‑apoptotic genes Bax and Bak, alongside the activation of caspase‑9, poly (ADP‑ribose) polymerase (PARP), and the release of cytochrome c. Furthermore, the specific JNK inhibitor SP600125 blocked chrysotile asbestos‑induced JNK activation and subsequent apoptosis, as assessed by both caspase‑9 cleavage and PARP activation. The results of the present study demonstrated that chrysotile asbestos induces intrinsic AEC apoptosis by a JNK‑dependent mechanism, and suggests a potential novel target for the modulation of chrysotile asbestos‑associated lung diseases.
authors.affiliation: Clinical Research Center, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors.forename: Tie
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center and Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Kamp
authors.affiliation: Clinical Research Center, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Clinical Research Center, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Yahong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Clinical Research Center, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Donghong
authors.initials: D
authors.lastname: Li
authors.affiliation: Clinical Research Center, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Lawei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Clinical Research Center, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: He
authors.affiliation: Clinical Research Center, Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D017632:Asbestos, Serpentine / Q000494:pharmacology*; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D017632:Asbestos, Serpentine; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D053453:Caspase 9