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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 241-248, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.4903

The Mitochondria-Regulated Death Pathway Mediates Asbestos-Induced Alveolar Epithelial Cell Apoptosis

Vijayalakshmi Panduri, Sigmund A. Weitzman, Navdeep Chandel and David W. Kamp

Department of Medicine, Divisions of Pulmonary and Critical Care Medicine and Hematology-Oncology, Northwestern University Feinberg School of Medicine; and Veterans Administration, Chicago Health Care System, Lakeside Division, Chicago, Illinois

Address correspondence to: David W. Kamp, Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, Tarry Building 14-707, 303 E. Chicago Ave., Chicago, IL 60611-3010. E-mail: d-kamp{at}nwu.edu

The mechanisms underlying asbestos-induced pulmonary toxicity are not fully understood. Alveolar epithelial cell (AEC) apoptosis by iron-derived reactive oxygen species (ROS) is one important mechanism implicated. The two major pathways regulating apoptosis include (i) the mitochondrial death (intrinsic) pathway caused by DNA damage, and (ii) the plasma-membrane death receptor (extrinsic) pathway. However, it is unknown whether asbestos activates either death pathway in AEC. We determined whether asbestos triggers AEC mitochondrial dysfunction by exposing cells (A549 and rat alveolar type II) to amosite asbestos and assessing mitochondrial membrane potential changes ({Delta}{psi}m) using a fluorometric technique involving tetremethylrhodamine ethyl ester (TMRE) and mitotracker green. Unlike inert particulates (titanium dioxide and glass beads), amosite asbestos caused dose- and time-dependent reductions in {Delta}{psi}m. Asbestos-induced {Delta}{psi}m was associated with the release of cytochrome c from the mitochondria to the cytoplasm as well as activation of caspase 9, a mitochondrial-activated caspase. In contrast, a lower level of caspase 8, the death receptor–activated caspase, was detected in asbestos-exposed AEC. An iron chelator (phytic acid or deferoxamine) or a hydroxyl radical scavenger (sodium benzoate) each blocked asbestos-induced reductions in {Delta}{psi}m and caspase 9 activation, suggesting a role for iron-derived ROS. Finally, Bcl-XL, a mitochondrial antiapoptotic protein that prevents cell death by preserving the outer mitochondrial membrane integrity, blocked asbestos-induced decreases in A549 cell {Delta}{psi}m and reduced apoptosis as assessed by DNA fragmentation. We conclude that asbestos-induced AEC apoptosis results from mitochondrial dysfunction, in part due to iron-derived ROS, which is followed by the release of cytochrome c and caspase 9 activation. Our findings suggest an important role for the mitochondria-regulated death pathway in the pathogenesis of asbestos-associated pulmonary toxicity.

Abbreviations: mitochondrial membrane potential changes, {Delta}{Psi}m • alveolar epithelial cells, AEC • alveolar type II, AT2 • Dulbecco's modified Eagle's medium, DMEM • dimethylsulfoxide, DMSO • dimethylthiourea, DMTU • DNA strand breaks, DNA-SB • fetal bovine serum, FBS • hydrogen peroxide, H2O2 • Hanks' balanced salt solution, HBSS • N-2-hydroxy-ethylpiperazine-N'-2-ethansulfonic acid, HEPES • mitochondrial intermembrane space, MIMS • mitotracker green, MITO • superoxide anion, O2- • hydroxyl radical, ·OH • phosphate-buffered saline, PBS • reactive oxygen species, ROS • titanium dioxide, TiO2 • tetremethylrhodamine ethyl ester, TMRE • tumor necrosis factor-{alpha}, TNF-{alpha} • terminal deoxynucleotidyl transferase-mediated deoxyuridine-5'-triphosphate-biotin nick end labeling, TUNEL




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