Particulate matter induces alveolar epithelial cell DNA damage and apoptosis: role of free radicals and the mitochondria.
Airborne particulate matter (PM) increases morbidity and mortality resulting from cardiopulmonary diseases including cancer. We hypothesized that PM is genotoxic to alveolar epithelial cells (AEC) by causing DNA damage and apoptosis. PM caused dose-dependent AEC DNA strand break formation, reductions in mitochondrial membrane potential (Delta psi m), caspase 9 activation, and apoptosis. An iron chelator and a free radical scavenger prevented these effects. Finally, overexpression of Bcl-xl, a mitochondrial anti-apoptotic protein, blocked PM-induced Delta psi m and DNA fragmentation. We conclude that PM causes AEC DNA damage and apoptosis by mechanisms that involve the mitochondria-regulated death pathway and the generation of iron-derived free radicals.
Upadhyay
Daya
D
Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, and Department of Medicine, Veterans Administration Chicago Healthcare System, Lakeside Division, Chicago, IL 60611, USA.
Panduri
Vijayalakshmi
V
Ghio
Andrew
A
Kamp
David W
DW
D017209:Apoptosis; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007501:Iron / Q000494:pharmacology; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species; D013696:Temperature; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D002614:Chelating Agents; D005609:Free Radicals; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D007501:Iron; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases