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p53 Mediates Particulate Matter–induced Alveolar Epithelial Cell Mitochondria-regulated Apoptosis

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine and Jesse Brown Veterans Administration Medical Center–Lakeside Division, Chicago, Illinois; and National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park, North Carolina

Correspondence and requests for reprints should be addressed to David W. Kamp, M.D., Northwestern University, Feinberg School of Medicine, Division of Pulmonary and Critical Care Medicine, McGaw M-2300, 240 East Huron Street, Chicago, IL 60611–3010. 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 (AT) 2 cells.

Methods: A well-characterized form of urban PM was used to determine whether it induces mitochondrial dysfunction (mitochondrial membrane potential change [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-, 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 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-° cells that are incapable of mitochondrial reactive oxygen species production were protected against PM-induced 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.

Key Words: apoptosis • mitochondria • p53 • particulate matter • reactive oxygen species

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Exposure to airborne particulate matter (PM) causes lung cancer by unclear mechanisms; however, evidence implicates that malignant cells arise from deficient programmed cell death (apoptosis) as well as mutations in p53, a critical DNA damage response protein that is a tumor suppressor. What This Study Adds to the Field Our findings that p53 mediates PM alveolar epithelial cell apoptosis in both human and rat cells in part by activating the intrinsic (mitochondria) death pathway suggest a novel interaction between p53 and the mitochondria that is relevant to the pathogenesis of lung cancer from air pollution.

 

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