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ULTRAFINE PARTICLE DISPOSITION IN THE HEALTHY AND MILDLY OBSTRUCTED LUNG
Citation:
Brown, J. S., K. L. Zeman, W. D. Bennett, AND C S. Kim. ULTRAFINE PARTICLE DISPOSITION IN THE HEALTHY AND MILDLY OBSTRUCTED LUNG. Presented at International Society for Aerosols in Medicine, Interlaken, Switzerland, September 2001.
Description:
ABSTRACT
We have shown previously that EGF receptor signaling is triggered by metals associated with ambient air particles. Specifically, we demonstrated that As, Zn and V activated the EGF receptor tyrosine kinase and the downstream kinases, MEK1/2 and ERK1/2. In this study, we examined the role of Ras in EGF receptor signaling and the NF B activation pathway, and the possible interaction between these two signaling pathways in a human airway epithelial cell line (BEAS-2B) exposed to As, V or Zn. Each metal significantly increased Ras activity, and this effect was inhibited by the EGF receptor tyrosine kinase inhibitor, PD153035. Adenoviral-mediated overexpression of a dominant-negative mutant form of Ras(N17) significantly blocked MEK1/2 or ERK1/2 phosphorylation in As-, Zn-, or V-exposed BEAS-2B cells, but caused little inhibition of V-, Zn- or EGF-induced EGF receptor tyrosine phosphorylation. This confirmed Ras as an important effector in EGF receptor signaling. Interestingly, V, but not As, Zn, or EGF, induced I B breakdown and NF B DNA-binding. Moreover, the EGF receptor tyrosine kinase inhibitor, PD153035, and overexpression of Ras(N17) significantly blocked V-induced I B breakdown and NF B activation, while inhibition of MEK activity with PD98059 failed to do so. In summary, exposure to As, Zn, and V initiated EGF receptor signaling and Ras-dependent activation of MEK1/2 and ERK1/2, but only V induced Ras-dependent NF B nuclear translocation. EGF receptor signaling appears to cross-talk with NF B signaling at the level of Ras, but additional signals appear necessary for NF B activation. Taken together, these data suggested that in V-treated BEAS-2B cells Ras-dependent signaling is essential, but not sufficient for activation of NF B.