Article Text

  1. S. Soberanes1,2,
  2. V. Panduri1,2,
  3. G. S. Budinger1,
  4. D. W. Kamp1,2
  1. 1Northwestern University Feinberg School of Medicine, Chicago, IL
  2. 2VA Chicago-Lakeside


Airborne particulate matter (PM) increases morbidity and mortality resulting from cardiopulmonary diseases including lung cancer and chronic obstructive lung disease. PM induces alveolar epithelial cell (AEC) DNA damage and apoptosis in part by generating iron-derived reactive oxygen species (ROS) and activating the mitochondria-regulated death pathway. Since p53 is critically involved in the cellular DNA damage response that can result in mitochondrial dysfunction, we determined whether transcriptional activation of p53 is required for PM-induced A549 cell apoptosis. We found that pifithrin (30 μM for 24 h), an inhibitor of p53 transcriptional activation, blocked PM (50 μg/cm2) induced caspase 9 activation and apoptosis, as assessed by annexin V staining and DNA fragmentation (Table). Similar findings were noted in A549 cells overexpressing the E6 oncoprotein, which also blocks p53 transcription (data not shown). Finally, we found that PM caused the translocation of BAX, a pro-apoptotic Bcl-2 family member, from the cytosol to the mitochondrial membrane that was inhibited in cells treated with pifithrin. Thus, p53 mediates PM-induced AEC mitochondrial-dependent apoptosis. These data suggest an important role for p53 in the pathogenesis of PM-induced pulmonary toxicity in part by causing mitochondrial dependent apoptosis. Funded by Veterans Affairs Merit Review (D.W.K.); NIH-K08 (G.S.B.).

Table 1.

Pifithrin Blocks PM‐Induced Caspase 9 Activation and Apoptosis

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