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


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.
Soberanes
Saul
S
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 East Huron Street, Chicago, IL 60611-3010, USA.
Panduri
Vijayalakshmi
V
Mutlu
Gökhan M
GM
Ghio
Andrew
A
Bundinger
G R Scott
GR
Kamp
David W
DW
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D052160:Benzothiazoles / Q000494:pharmacology; D002478:Cells, Cultured; D053938:DNA Fragmentation; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D052638:Particulate Matter / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014178:Translocation, Genetic / Q000502:physiology
D052160:Benzothiazoles; D052638:Particulate Matter; D017382:Reactive Oxygen Species; D014050:Toluene; C121565:pifithrin