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Toxicology and Mechanisms of Lung Responses to Carbon Nanotube Exposures

Frank, Evan A
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1448037426

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Toxicology (Environmental Health).
Carbon nanotubes (CNTs) are carbon-based fiber nanoparticles with wide-ranging applications in technology and industry. The extensive utility of CNTs has led to dramatic increases in their manufacture and distribution, resulting in the potential for occupational and environmental exposures in human populations. CNTs can become agitated into aerosols and are thought to pose a threat as inhaled toxicants due to their insoluble nature, high aspect ratio, and biopersistence. CNTs are often compared to asbestos, with which they share the aforementioned attributes. Toxicological studies of CNTs are advancing the knowledge of health risks using experimental exposure models, but the cellular and molecular mechanisms of toxic responses are largely unknown. In this work, we characterized a CNT test material for physiochemical attributes and established in vivo mouse models of acute and subchronic exposure in lung to show that CNT exposures caused acute and chronic inflammation, lung tissue lesions consisting of granulomatous inflammation and type II pneumocyte hyperplasia, and increased interstitial collagen. In order to investigate the underlying causes of these responses, we tested the hypothesis that lung responses to CNTs are mediated by specific effector cells and cell type-specific mechanisms. In addition, we investigated whether genetic background may modify responses to CNTs. Usingin vivo models incorporating cell type-specific depletion and repopulation, we demonstrated that alveolar macrophages (AMs) act as specific effector cells of acute inflammatory responses to CNT exposure. We then used in vitro assays in AM cell cultures to screen for AM-specific molecular mechanisms mediating the production of cytokines in response to in vitro CNT exposure. In this way, the MyD88 adaptor molecule was found to be critical in AM in vitro responses. We then recapitulated this finding in vivo, demonstrating that AM-specific MyD88 is critical for AM effector functions in acute CNT exposures. In further work, we used an inter-strain survey of inbred mouse strains to demonstrate that genetic background modifies subchronic lung responses to CNTs. Specifically, we identified C57Bl/6 and DBA/2 strains as sensitive and resistant to CNT exposures, respectively. Overall, this work breaks new ground in the investigation of CNT toxicology and may contribute to: 1) development of targeted intervention-based therapies which may aid in management of toxic CNT exposures, and 2) identification of susceptible genetic backgrounds in human populations exposed to CNTs.
Jagjit Yadav, Ph.D. (Committee Chair)
Daniel Prows, Ph.D. (Committee Member)
Susan Kasper, Ph.D. (Committee Member)
Ian Paul Lewkowich, Ph.D. (Committee Member)
165 p.
Toxicology
carbon nanotubes; nanotoxicology; lung; toxicologic pathology; fiber toxicology

Recommended Citations

Citations

  • Frank, E. A. (2015). Toxicology and Mechanisms of Lung Responses to Carbon Nanotube Exposures [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1448037426

    APA Style (7th edition)

  • Frank, Evan. Toxicology and Mechanisms of Lung Responses to Carbon Nanotube Exposures. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1448037426.

    MLA Style (8th edition)

  • Frank, Evan. "Toxicology and Mechanisms of Lung Responses to Carbon Nanotube Exposures." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1448037426

    Chicago Manual of Style (17th edition)

ucin1448037426
260
© 2015, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.