Asbestos-induced alveolar epithelial cell apoptosis: The role of endoplasmic reticulum stress response

David W. Kamp*, Gang Liu, Paul Cheresh, Seok Jo Kim, Amanda Mueller, Anna P. Lam, Humberto Trejo, David Williams, Sandhya Tulasiram, Margaret Baker, Karen Ridge, Navdeep S. Chandel, Rohinee Beri

*Corresponding author for this work

Research output: Contribution to journalArticle

36 Scopus citations

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 mitochondriaregulated (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 as bestos fibers increased AEC mRNA and protein expression of E Rstress proteins involvedin the unfolded protein response, such as inositol-requiring kinase (IRE) 1 and X-box-binding protein-1, as wellas ERCa2+ release,as assessedby aFURA-2 assay. Eukarion-134, a superoxide dismutase/catalase mimetic, as well as overexpression of Bcl-X L in A549 cells eachattenuate asbestos-induced AECERstress (IRE-1 and X-box-binding protein-1 protein expression; ER Ca2+ release) and apoptosis. Thapsigargin, a known ER stress inducer, augments AECapoptosis, and eukarion-134orBcl-XL overexpression are protective. Finally, 4-phenylbutyric acid, a chemical chaperone that attenuatesERstress, blocksasbestos- and thapsigargin-induced AEC IRE-1 protein expression, but does not reduce ER Ca2+ release or apoptosis. These results showthat asbestos triggers an AECER stress response and subsequent intrinsic apoptosis thatismediatedinpart by ER Ca2+ release.

Original languageEnglish (US)
Pages (from-to)892-901
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume49
Issue number6
DOIs
StatePublished - Dec 1 2013

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Keywords

  • Alveolar epithelium
  • Apoptosis
  • Asbestos
  • Endoplasmic reticulum
  • Mitochondria

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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