TY - JOUR
T1 - p53 mediates particulate matter-induced alveolar epithelial cell mitochondria-regulated apoptosis
AU - Soberanes, Saul
AU - Panduri, Vijayalakshmi
AU - Mutlu, Gökhan M.
AU - Ghio, Andrew
AU - Bundinger, G. R.Scott
AU - Kamp, David W.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/12/1
Y1 - 2006/12/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Mitochondria
KW - Particulate matter
KW - Reactive oxygen species
KW - p53
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U2 - 10.1164/rccm.200602-203OC
DO - 10.1164/rccm.200602-203OC
M3 - Article
C2 - 16946128
AN - SCOPUS:33845535662
VL - 174
SP - 1229
EP - 1238
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 11
ER -