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Pre-Conditioning the Airways of Mice with Bleomycin Increases the Efficiency of Orthotopic Lung Cancer Cell Engraftment
Published on: June 28, 2018
Mitochondrial DNA-depleted A549 cells are resistant to bleomycin
Sukhdev S Brar1, Joel N Meyer, Carl D Bortner
1Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Summary
Bleomycin lung injury primarily damages mitochondrial DNA (mtDNA) more than nuclear DNA (nDNA) in alveolar cells. Depleting mtDNA increases cell resistance to bleomycin toxicity, suggesting new therapeutic targets for lung fibrosis.
Area of Science:
- Cell Biology
- Toxicology
- Pulmonary Medicine
Background:
- Alveolar epithelial cells are the main targets of bleomycin-induced lung injury, a process leading to interstitial fibrosis.
- The precise molecular mechanisms behind bleomycin's damage, including reactive oxygen species generation and DNA damage, remain unclear.
Purpose of the Study:
- To investigate the differential effects of bleomycin on mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) in human alveolar epithelial A549 cells.
- To explore the role of mtDNA in bleomycin-induced apoptosis and cellular toxicity.
Main Methods:
- Treatment of human alveolar epithelial A549 cells and mtDNA-depleted (ρ(0)) A549 cells with bleomycin.
- Assessment of reactive oxygen species production, DNA damage (mtDNA and nDNA), apoptosis markers (caspase-3, PARP cleavage), and protein kinase D1 (PKD1) activation.
- Comparison of cell survival rates between A549 and A549 ρ(0) cells post-bleomycin exposure.
Main Results:
- Bleomycin increased reactive oxygen species, DNA damage, and apoptosis in A549 cells.
- Bleomycin induced significantly more mtDNA damage than nDNA damage.
- mtDNA-depleted A549 cells showed no caspase-3 or PKD1 activation and exhibited higher survival rates after bleomycin treatment compared to parent A549 cells.
Conclusions:
- Bleomycin-induced lung injury is heavily dependent on mtDNA damage.
- Depletion of mtDNA confers resistance to bleomycin toxicity by impairing mitochondria-dependent apoptotic pathways.
- Targeting mtDNA or mitochondrial pathways may offer a novel therapeutic strategy for bleomycin-induced lung fibrosis.
