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ASBESTOS-INDUCED ACTIVATION OF SIGNALING PATHWAYS IN HUMAN BRONCHIAL EPITHELIAL CELLS
Citation:
Wang, X., J M. Samet, AND A J. Ghio. ASBESTOS-INDUCED ACTIVATION OF SIGNALING PATHWAYS IN HUMAN BRONCHIAL EPITHELIAL CELLS. Presented at American Thoracic Society, Orlando, Fl, May 21-26, 2004.
Description:
Title: Asbestos-Induced Activation of Signaling Pathways in Human
Bronchial Epithelial Cells
X. Wang, MD 1, J. M. Samet, PhD 2 and A. J. Ghio, MD 2. 1 Center for
Environmental Medicine, Asthma and Lung Biology, University of North
Carolina, Chapel Hill, NC, United States and 2 Human Studies Division,
NHEERL, US EPA, Chapel Hill, NC, United States .
The intracellular signaling mechanisms activated by asbestos exposure of
airway epithelial cells are not well characterized. We hypothesized that
ROS generated by asbestos results in the activation of the epidermal
growth factor receptor (EGFR) signaling pathway. In this study, the effect
of noncytotoxic exposure of crocidolite asbestos fiber on activation od
the EGFR and its downstream elements in the human airway epithelial cell
line BEAS 2B was examined. Western blotting using phsopho-specific
antibodies demonstrated that crocidolite exposure induced rapid
phosporylation of EGFR, MEK1/2, and ERK 1/2. The selective EGFR tyrosine
kinase inhibitor PD153035 markedly abrogated crocidolite-induced
phosphorylation of ERK1/2 as well as that of the upstream signaling
intermediates MEK1/2 and EGFR. Similarly, the specific MEK1 kinase
activity inhibitor PD98059 attenuated phosphorylation of ERK1/2 induced by
crocidolite treatment of BEAS 2B cells. Furthermore, the
crocidolite-induced phosphorylation of EGFR, MEK1/2 and ERK1/2 was
significantly blocked by an antibody directed against the ligand binding
site of the EGF receptor. Finally, the effect of crocidolite-induced EGFR
phosphorylation was reduced by adenoviral-mediated overexpression of SOD
and catalase, implicating the involvement of reactive oxygen species in
EGFR signaling activated by crocidolite exposure. Together, these results
show that crocidolite asbestos causes the phosphorylation and functional
activation of EGFR signaling to downstream signaling elements in BEAS
cells, and suggest that the mechanism the mechanism of action involves the
generation of reactive oxygen species. These findings shed important
insight on the effects of asbestos exposure on the airway epithelium. This
abstract of a proposed presentation does not necessarily reflect EPA
policy.