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.
Methods
A well-characterized form of urban PM was used to determine whether it induces mitochondrial dysfunction (mitochondrial membrane potential change [DeltaPsi m] 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-alpha, 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
Objective
We determined whether p53 is required for PM-induced apoptosis in both human and rodent alveolar type (AT) 2 cells.
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 DeltaPsi m, 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-rho degrees cells that are incapable of mitochondrial reactive oxygen species production were protected against PM-induced DeltaPsi m, 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.