TY - JOUR
T1 - Asbestos-induced alveolar epithelial cell apoptosis
T2 - The role of endoplasmic reticulum stress response
AU - Kamp, David W.
AU - Liu, Gang
AU - Cheresh, Paul
AU - Kim, Seok Jo
AU - Mueller, Amanda
AU - Lam, Anna P.
AU - Trejo, Humberto
AU - Williams, David
AU - Tulasiram, Sandhya
AU - Baker, Margaret
AU - Ridge, Karen
AU - Chandel, Navdeep S.
AU - Beri, Rohinee
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
KW - Alveolar epithelium
KW - Apoptosis
KW - Asbestos
KW - Endoplasmic reticulum
KW - Mitochondria
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U2 - 10.1165/rcmb.2013-0053OC
DO - 10.1165/rcmb.2013-0053OC
M3 - Article
C2 - 23885834
AN - SCOPUS:84890024018
SN - 1044-1549
VL - 49
SP - 892
EP - 901
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 6
ER -