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Published ahead of print on August 31, 2006, doi:10.1164/rccm.200602-203OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 11, December 2006, 1229-1238

A more recent version of this article appeared on December 1, 2006
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Submitted on February 10, 2006
Accepted on August 31, 2006

P53 Mediates Particulate Matter-Induced Alveolar Epithelial Cell Mitochondria-Regulated Apoptosis

Saul Soberanes1, Vijayalakshmi Panduri1, Ghokhan M Mutlu1, Andrew Ghio2, G.R. Scott Budinger1, and David W Kamp1*

1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine and Jesse Brown Veterans Administration Medical Center: Lakeside Division, Chicago, IL, USA, 2 EPA, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, USA

* To whom correspondence should be addressed. E-mail: d-kamp{at}northwestern.edu.

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 II cells. Methods A well- characterized form of urban PM was used to determine whether it induces mitochondrial dysfunction (mitochondrial membrane potential change [{Delta}{psi}m] and caspase 9 activation), p53 protein and mRNA expression, and apoptosis (DNA fragmentation and annexin V staining)in vitro using A549 cells as well as primary isolated human and rat alveolar type II 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). The in vivo effects of PM in mice 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 {Delta}{psi}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 alveolar type II cells. A549-{rho}° cells that are incapable of mitochondrial ROS production were protected against PM- induced {Delta}{psi}m, p53 expression and apoptosis. In mice, PM induced p53 expression and apoptosis at the broncho-alveolar 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.
Key words: particulate matter, p53, reactive oxygen species, mitochondria, apoptosis




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