Ultrafine airborne particles cause increases in protooncogene expression and proliferation in alveolar epithelial cells.

Exposure to ambient particulate matter (PM) is linked to increases in respiratory morbidity and exacerbation of cardiopulmonary diseases. However, the important components of PM and their mechanisms of action in lung disease are unclear. We demonstrate the development of dose-related proliferation and apoptosis after exposure of an alveolar epithelial cell line (C10) to PM or to ultrafine carbon black (ufCB), a component of PM. Ribonuclease protection assays demonstrated that increases in mRNA levels of the early response protooncogenes c-jun, junB, fra-1, and fra-2 accompanied cell proliferation at low concentrations of PM whereas apoptotic concentrations of PM caused transient increases in expression of fos and jun family members and dose responsive increases in mRNA levels of receptor-interacting protein, Fas-associated death domain, and caspase-8. Significant increases in steady-state mRNA levels of protooncogenes and apoptosis-associated genes, TNFR-associated death domain, and Fas were also observed after exposure of epithelial cells to ufCB, but not fine carbon black or glass beads, respectively, suggesting that the ultrafine particulate component of PM is critical to its biological activity.

[1]  B. Mossman,et al.  Use of transgenic luciferase reporter mice to determine activation of transcription factors and gene expression by fibrogenic particles. , 2001, Chest.

[2]  P. Vacek,et al.  Different accumulation of activated extracellular signal-regulated kinases (ERK 1/2) and role in cell-cycle alterations by epidermal growth factor, hydrogen peroxide, or asbestos in pulmonary epithelial cells. , 2001, American journal of respiratory cell and molecular biology.

[3]  J. Bravman,et al.  Silica-induced activation of c-Jun-NH2-terminal amino kinases, protracted expression of the activator protein-1 proto-oncogene, fra-1, and S-phase alterations are mediated via oxidative stress. , 2001, Cancer research.

[4]  P. Vacek,et al.  Inhaled particulate matter causes expression of nuclear factor (NF)-kappaB-related genes and oxidant-dependent NF-kappaB activation in vitro. , 2000, American journal of respiratory cell and molecular biology.

[5]  J. Kaiser.  Evidence Mounts That Tiny Particles Can Kill , 2000, Science.

[6]  M. O’Reilly,et al.  Tumor Necrosis Factor- α –Induced Lung Cell Expression of Antiapoptotic Genes TRAF1 and cIAP2 , 2000 .

[7]  K. BéruBé,et al.  Bioreactivity of carbon black and diesel exhaust particles to primary Clara and type II epithelial cell cultures. , 1999, Occupational and environmental medicine.

[8]  J. Habener,et al.  CHOP Enhancement of Gene Transcription by Interactions with Jun/Fos AP-1 Complex Proteins , 1999, Molecular and Cellular Biology.

[9]  B. Mossman,et al.  Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis. , 1999, The American journal of physiology.

[10]  S. Nagata,et al.  Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. , 1999, The Journal of clinical investigation.

[11]  W. Mcdonnell,et al.  Long-term inhalable particles and other air pollutants related to mortality in nonsmokers. , 1999, American journal of respiratory and critical care medicine.

[12]  A. Churg,et al.  Ambient particulate matter causes activation of the c-jun kinase/stress-activated protein kinase cascade and DNA synthesis in lung epithelial cells. , 1998, Cancer research.

[13]  A. Churg,et al.  Mechanisms in the pathogenesis of asbestosis and silicosis. , 1998, American journal of respiratory and critical care medicine.

[14]  L. Dwyer-Nield,et al.  Mouse lung epithelial cell lines--tools for the study of differentiation and the neoplastic phenotype. , 1997, Toxicology.

[15]  B. Mossman,et al.  Asbestos causes translocation of p65 protein and increases NF-kappa B DNA binding activity in rat lung epithelial and pleural mesothelial cells. , 1997, The American journal of pathology.

[16]  B. Mossman,et al.  Asbestos causes stimulation of the extracellular signal-regulated kinase 1 mitogen-activated protein kinase cascade after phosphorylation of the epidermal growth factor receptor. , 1996, Cancer research.

[17]  David Baltimore,et al.  An Essential Role for NF-κB in Preventing TNF-α-Induced Cell Death , 1996, Science.

[18]  J. Magae,et al.  Apoptosis is observed in mesothelial cells after exposure to crocidolite asbestos. , 1996, American journal of respiratory cell and molecular biology.

[19]  S. Steinberg,et al.  Altered cJUN expression: an early event in human lung carcinogenesis. , 1996, Cancer research.

[20]  B. Mossman,et al.  Transcriptional activation of the proto-oncogene c-jun by asbestos and H2O2 is directly related to increased proliferation and transformation of tracheal epithelial cells. , 1995, Cancer research.

[21]  N. Heintz,et al.  Persistent induction of c-fos and c-jun expression by asbestos. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Karin,et al.  The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. , 1991, Biochimica et biophysica acta.

[23]  S. Patierno,et al.  Apoptosis: inhibitor or instigator of carcinogenesis? , 1996, Cancer investigation.

[24]  T. Harris,et al.  Tumor necrosis factor alpha modulates mitogenic responses of human cultured airway smooth muscle. , 1995, American journal of respiratory cell and molecular biology.

[25]  B. Weiss,et al.  Association of particulate air pollution and acute mortality: involvement of ultrafine particles? , 1995, Inhalation toxicology.