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Asbestos-induced alveolar epithelial cell apoptosis:Role of mitochondrial dysfunction caused by iron-derived free radicals

  • David W. Kamp
  • Vijayalakshmi Panduri
  • Sigmund A. Weitzman
  • Navdeep Chandel
Chapter
  • 412 Downloads
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 37)

Abstract

Asbestos causes asbestosis and malignancies by mechanisms that are not fully understood. Alveolar epithelial cell (AEC) injury by iron-derived reactive oxygen species (ROS) is one important mechanism implicated. We previously showed that iron-catalyzed ROS in part mediate asbestos-induced AEC DNA damage and apoptosis. Mitochondria have a critical role in regulating apoptosis after exposure to agents causing DNA damage but their role in regulating asbestos-induced apoptosis is unknown. To determine whether asbestos causes AEC mitochondrial dysfunction, we exposed A549 cells to amosite asbestos and assessed mitochondrial membrane potential changes (ΔΨm) using a fluorometric technique involving tetremethylrhodamine ethyl ester (TMRE) and mitotracker green. We show that amosite asbestos, but not an inert particulate, titanium dioxide, reduces AR after a 4 h exposure period. Further, the AT after 4 h was inversely proportional to the levels of apoptosis noted at 24 h as assessed by nuclear morphology as well as by DNA nucleosome formation. A role for iron-derived ROS was suggested by the finding that phytic acid, an iron chelator, blocked asbestos-induced reductions in A549 cell ΔΨmand attenuated apoptosis. Finally, overexpression of Bcl-xl, an anti-apoptotic protein that localizes to the mitochondria, prevented asbestos-induced decreases in A549 cell ΔΨmafter 4 h and diminished apoptosis. We conclude that asbestos alters AEC mitochondrial function in part by generating iron-derived ROS, which in turn can result in apoptosis. This suggests that the mitochondrial death pathway is important in regulating pulmonary toxicity from asbestos. (Mol Cell Biochem 234/235: 153–160, 2002)

Key words

DNA damage pulmonary epithelium oxidants free radicals mitochondria apoptosis 

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Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • David W. Kamp
    • 1
  • Vijayalakshmi Panduri
    • 1
  • Sigmund A. Weitzman
    • 2
  • Navdeep Chandel
    • 1
  1. 1.Lakeside Division and the Department of Medicine, Divisions of Pulmonary and Critical Care MedicineVeterans Administration Chicago Health Care SystemChicagoUSA
  2. 2.Hematology-OncologyNorthwestern University Medical SchoolChicagoUSA

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