p53 mediates particulate matter-induced alveolar epithelial cell mitochondria-regulated apoptosis

Saul Soberanes, Vijayalakshmi Panduri, Gökhan M. Mutlu, Andrew Ghio, G. R.Scott Bundinger, David W. Kamp*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Rationale: Exposure to particulate matter (PM) causes lung cancer by mechanisms that are unknown, but p53 dysfunction is implicated. Objective: We determined whether p53 is required for PM-induced apoptosis in both human and rodent alveolar type (AT) 2 cells. Methods: A well-characterized form of urban PM was used to determine whether it induces mitochondrial dysfunction (mitochondrial membrane potential change [ΔΨm] and caspase-9 activation), p53 protein and mRNA expression, and apoptosis (DNA fragmentation and annexin V staining) in vitro using A549 cells and primary isolated human and rat AT2 cells. The role of p53 was assessed using inhibitors of p53-dependent transcription, pifithrin-α, and a genetic approach (overexpressing E6 or dominant negative p53). In mice, the in vivo effects of PM causing p53 expression and apoptosis were assessed 72 h after a single PM intratracheal instillation. Measurements and Main Results: PM-induced apoptosis in A549 cells was characterized by increased p53 mRNA and protein expression, mitochondrial translocation of Bax and p53, a reduction in ΔΨm, and caspase-9 activation, and these effects were blocked by inhibiting p53-dependent transcription. Similar findings were noted in primary isolated human and rat AT2 cells. A549-ρ° cells that are incapable of mitochondrial reactive oxygen species production were protected against PM-induced ΔΨm, p53 expression, and apoptosis. In mice, PM induced p53 expression and apoptosis at the bronchoalveolar duct junctions. Conclusions: These data suggest a novel interaction between p53 and the mitochondria in mediating PM-induced apoptosis that is relevant to the pathogenesis of lung cancer from air pollution.

Original languageEnglish (US)
Pages (from-to)1229-1238
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Volume174
Issue number11
DOIs
StatePublished - Dec 1 2006

Keywords

  • Apoptosis
  • Mitochondria
  • Particulate matter
  • Reactive oxygen species
  • p53

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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