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MEMBRANE PERMEABILITY AS A DETERMINANT OF ZN2+-INDUCED SIGNALING IN HUMAN AIRWAY EPITHELIAL CELLS
Citation:
Silbajoris, R, J. Samet, D. Graff, P A. Bromberg, AND T. Tal. MEMBRANE PERMEABILITY AS A DETERMINANT OF ZN2+-INDUCED SIGNALING IN HUMAN AIRWAY EPITHELIAL CELLS. Presented at Society of Toxicology (SOT) annual meeting, New Orleans, LA, March 06 - 10, 2005.
Description:
Zinc (Zn2+) is an essential micronutrient but also a common metallic constituent of ambient air particulate matter (PM) that may play a role in PM-induced adverse health effects. In vivo and in vitro studies have shown that Zn2+ exposure induces inflammatory responses in the airways. We have previously shown that exposure to Zn2+ results in activation of multiple intracellular signaling intermediates, including the epidermal growth factor receptor (EGFR), in a variety of cell types. Based on this variability, we hypothesized that cellular permeability is a factor limiting the magnitude of signal transduction activation induced by Zn2+. To test this hypothesis, we used the Zn2+ ionophore pyrithione to permeabilize the human bronchial epithelial cell line BEAS and primary human airway epithelial cell cultures (HAEC) to Zn2+ and measured levels of EGFR phosphorylation. Treatment of BEAS cells with sub- to low-micromolar concentrations of pyrithione in the presence of 250 M extracellular Zn2+ resulted in dose-dependent increases in Zn2+-specific fluorescence as determined by fluorometry using FURA-2. Lysophosphatidylcholine, a physiologically relevant permeabilizing agent, also increased Zn2+ permeability in BEAS cells. Co-administration of 4 M pyrithione markedly potentiated Zn2+-induced EFGR phosphorylation at the auto- and trans-phosphorylation sites Y1068 and Y845, respectively, in HAEC. These findings show that Zn2+ acts through an intracellular target to effect EGFR phosphorylation. Further, cellular permeability is a critical determinant of cellular responsiveness to signal initiation by exposure to Zn2+. Pathophysiological alterations in cellular homeostasis that may result in increased permeability to Zn2+ influx and sensitize HAEC to the effects of inhaled Zn compounds are presently under investigation. Additionally, the possibility that xenobiotics with pyrithione-like properties exist in PM is also being studied. THIS ABSTRACT OF A PROPOSED PRESENTATION DOES NOT NECESSARILY REFLECT EPA POLICY.