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Ambient Particulate Matter Causes Activation of the c-jun Kinase/Stress-activated Protein Kinase Cascade and DNA Synthesis in Lung Epithelial Cells¹

Departments of Pathology [C. T., E. W., A. B. C., B. M.], Civil and Mechanical Engineering [D. H.], and Biostatistics [P. V.], University of Vermont, Burlington, Vermont 05405; School of Molecular and Medical Biosciences, University of Cardiff, Cardiff CF1 3US, United Kingdom [K. B.], Department of Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 2B5 Canada [A. C.]; Miami Valley Laboratories, Procter & Gamble, Inc., Cincinnati, Ohio 45239 [K. D.]; and Institute of Environmental Medicine, New York University Medical Center, Long Meadow Road, Tuxedo, New York 10987 [T. G.]

Numerous epidemiological studies have demonstrated a positive association between ambient air pollution and adverse health effects including respiratory morbidity, asthma, and lung cancer. It has been suggested in some experimental studies that airborne particulate matter (PM) can produce inflammatory effects, but nothing is known about the possible proliferative and carcinogenic effects of these particles on cells of the lung. We show here that exposure of pulmonary epithelial cells, a cell type affected in acute lung injury, asthma, and lung carcinomas, to nontoxic concentrations of PM in vitro results in increases in c-jun kinase activity, levels of phosphorylated cJun immunoreactive protein, and transcriptional activation of activator protein-1-dependent gene expression. These changes are accompanied by elevations in numbers of cells incorporating 5'-bromodeoxyuridine, a marker of unscheduled DNA synthesis and/or cell proliferation. Data here are the first to demonstrate that interaction of ambient PM with target cells of the lung initiates a cell signaling cascade related causally to aberrant cell proliferation and carcinogenesis.

¹ This research was supported by a Special Emphasis Research Career Award from National Institute for Occupational Safety and Health (to C. T.), Grants ES0649 and 09213 from National Institute of Environmental Health Sciences (to B. T. M.), Grant HL-39469 from the National Heart, Lung, and Blood Institute (to B. T. M.), Grants MT6097, MT8051, and M77820 from the Medical Research Council of Canada (to A. C.), Health Effects Institute Contract 95-8, Grant G7061234 from the Environmental Protection Agency, and Grant ES0256 from the National Institute of Environmental Health Sciences.

² To whom requests for reprints should be addressed, at the University of Vermont, Department of Pathology, Burlington, VT 05405. Phone: (802) 656-0382; Fax: (802) 656-8892; E-mail: ctimblin@zoo.uvm.edu.

Received 7/16/98. Accepted 8/24/98.

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