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P53 mediates amosite asbestos-induced alveolar epithelial cell mitochondria-regulated apoptosis

Vijayalakshmi Panduri1, Sailesh Surapureddi, Saul Soberanes

  • 1Northwestern University Feinberg School of Medicine, Pulmonary and Critical Care Medicine, McGaw M-2300, 240 E. Huron St., Chicago, IL 60611-3010, USA.

American Journal of Respiratory Cell and Molecular Biology
|December 17, 2005
PubMed

Insights

Asbestos exposure triggers DNA damage and cell death in lung cells via p53-dependent pathways. Inhibiting p53 activation protects against asbestos-induced apoptosis, suggesting new therapeutic targets for lung diseases.

Area of Science:

  • Cell Biology
  • Toxicology
  • Molecular Biology

Background:

  • Asbestos exposure induces pulmonary toxicity through reactive oxygen species (ROS) and DNA damage.
  • Mitochondria-regulated (intrinsic) cell death pathways are implicated in asbestos-induced alveolar epithelial cell (AEC) apoptosis.
  • The tumor suppressor protein p53 plays a critical role in DNA damage response and intrinsic cell death induction.

Purpose of the Study:

  • To investigate the role of p53-dependent transcriptional activity in asbestos-induced AEC mitochondrial dysfunction and apoptosis.
  • To elucidate the interactive effects between p53 and mitochondria in asbestos-related lung pathogenesis.

Main Methods:

  • Utilized inhibitors of p53 transcriptional activation (pifithrin, E6 protein) to assess their effects on asbestos-induced apoptosis.
  • Measured mitochondrial membrane potential (ΔPsim), caspase 9 activation, and apoptosis in AECs.
  • Assessed p53 promoter activity, mRNA, protein expression, and mitochondrial translocation of p53 and Bax.
  • Examined the impact of ROS-deficient cells (rho(0)-A549) and phytic acid on asbestos-induced p53 activation.
  • Evaluated asbestos-induced p53 expression in rat lung tissues.

Main Results:

  • Inhibitors of p53 transcriptional activation blocked asbestos-induced changes in mitochondrial membrane potential, caspase 9 activation, and apoptosis.
  • Asbestos exposure led to increased p53 promoter activity, mRNA, protein levels, and mitochondrial translocation of p53 and Bax.
  • p53 activation by asbestos was inhibited by pifithrin, E6, phytic acid, and in cells lacking mitochondrial ROS production.
  • Asbestos exposure increased p53 expression in rat lung tissues, an effect prevented by phytic acid.

Conclusions:

  • p53-dependent transcription pathways mediate asbestos-induced apoptosis in alveolar epithelial cells via mitochondrial pathways.
  • There is a significant interaction between p53 and mitochondria in the pathogenesis of asbestos-induced pulmonary toxicity.
  • These findings have potential implications for understanding and treating pulmonary fibrosis and lung cancer.

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