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    Analysis of the role of zinc, a major component of ambient Baltimore fine particulate matter, in eliciting cytokine and chemokine release and disrupting cellular tight junctions in vitro

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    Author
    Mitkus, Robert Joseph
    Advisor
    Squibb, Katherine S.
    Powell, Jan L.
    Date
    2004
    Type
    dissertation
    
    Metadata
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    Abstract
    The studies described in this dissertation were undertaken in order to address the primary hypothesis that the metal zinc contained in PM2.5 is responsible for the adverse health effects that are associated with human exposure to PM2.5 as reported in the epidemiological literature. Comparison of chemokine and cytokine release from A549 alveolar epithelial type II cells and RAW 264.7 monocytes, respectively, that were exposed to NIST Interim RM PM2.5, with that due to the larger NIST Standard Reference Material (SRM) 1648, led to the conclusion that cytotoxicity and soluble mediator release elicited by these two reference PM samples can be explained by differences in particle size and/or metal content. Single and multiple linear regression models were built to test the hypothesis that zinc was responsible for cytokine and chemokine release following treatment with ambient PM2.5 collected every half-hour or hour from a local site in Baltimore, MD. The regression models more accurately supported the hypothesis that multiple metals interacted with each other to cause this release. The third specific aim was to determine if exposure of cells to soluble Zn disrupts tight junctions (TJs) formed between A549 alveolar epithelial cells. Transepithelial electrical resistance measurements indicated that Cd exposure disrupted Us formed between A549 cells; but Zn, NIST Interim RM PM2.5 and SRM 1648 exposures did not. Immunofluorescence microscopy showed disruption of TJs only after treatment with EGTA. Overall, the results of this research have led to the conclusion that zinc alone cannot explain cytokine or chemokine release following exposure to ambient PM in vitro. It is more likely that other combinations of elements, such as Cd and Se, play a more important role in eliciting inflammatory mediator release, and that the mechanism of action of zinc alone does not include disruption of tight junctions. Future testing of the relationship between Zn and MCP-1 release on the disruption of epithelial tight junctions is warranted, however, based on the recent observation that the chemokine MCP-1 disrupts TJs formed between endothelial cells of the blood-brain barrier.
    Description
    University of Maryland, Baltimore. Epidemiology and Preventive Medicine. Ph.D. 2004
    Keyword
    Health Sciences, Toxicology
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1124
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    Theses and Dissertations School of Medicine
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