title: Asbestos-induced alveolar epithelial cell apoptosis. The role of endoplasmic reticulum stress response.
abstract: Asbestos exposure results in pulmonary fibrosis (asbestosis) and malignancies (bronchogenic lung cancer and mesothelioma) by mechanisms that are not fully understood. Alveolar epithelial cell (AEC) apoptosis is important in the development of pulmonary fibrosis after exposure to an array of toxins, including asbestos. An endoplasmic reticulum (ER) stress response and mitochondria-regulated (intrinsic) apoptosis occur in AECs of patients with idiopathic pulmonary fibrosis, a disease with similarities to asbestosis. Asbestos induces AEC intrinsic apoptosis, but the role of the ER is unclear. The objective of this study was to determine whether asbestos causes an AEC ER stress response that promotes apoptosis. Using human A549 and rat primary isolated alveolar type II cells, amosite asbestos fibers increased AEC mRNA and protein expression of ER stress proteins involved in the unfolded protein response, such as inositol-requiring kinase (IRE) 1 and X-box-binding protein-1, as well as ER Ca²(2+) release ,as assessed by a FURA-2 assay. Eukarion-134, a superoxide dismutase/catalase mimetic, as well as overexpression of Bcl-XL in A549 cells each attenuate asbestos-induced AEC ER stress (IRE-1 and X-box-binding protein-1 protein expression; ER Ca²(2+) release) and apoptosis. Thapsigargin, a known ER stress inducer, augments AEC apoptosis, and eukarion-134 or Bcl-XL overexpression are protective. Finally, 4-phenylbutyric acid, a chemical chaperone that attenuates ER stress, blocks asbestos- and thapsigargin-induced AEC IRE-1 protein expression, but does not reduce ER Ca²(2+) release or apoptosis. These results show that asbestos triggers an AEC ER stress response and subsequent intrinsic apoptosis that is mediated in part by ER Ca²(2+) release.
authors.affiliation: 1 Department of Medicine, Division of Pulmonary & Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center and Northwestern University Feinberg School of Medicine, Chicago, Illinois; and.
authors.forename: David W
authors.initials: DW
authors.lastname: Kamp
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Paul
authors.initials: P
authors.lastname: Cheresh
authors.forename: Seok-Jo
authors.initials: SJ
authors.lastname: Kim
authors.forename: Amanda
authors.initials: A
authors.lastname: Mueller
authors.forename: Anna P
authors.initials: AP
authors.lastname: Lam
authors.forename: Humberto
authors.initials: H
authors.lastname: Trejo
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.forename: Sandhya
authors.initials: S
authors.lastname: Tulasiram
authors.forename: Margaret
authors.initials: M
authors.lastname: Baker
authors.forename: Karen
authors.initials: K
authors.lastname: Ridge
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: Rohinee
authors.initials: R
authors.lastname: Beri
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D017639:Asbestos, Amosite / Q000633:toxicity*; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D012459:Salicylates / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; C494811:BCL2L1 protein, human; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; C433928:EUK-134; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D009942:Organometallic Compounds; D010654:Phenylbutyrates; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D012459:Salicylates; D014157:Transcription Factors; D051020:bcl-X Protein; D017639:Asbestos, Amosite; D051742:Transcription Factor CHOP; D019284:Thapsigargin; C075773:4-phenylbutyric acid; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases