A growing demand for information on the human health and environmental effects of materials produced using nanotechnology has led to a new area of investigation known as nanotoxicology. Research in this field has widespread implications in facilitating the medical applications of nanomaterials but also in addressing occupational and environmental toxicity concerns. Improving our understanding of these issues also has broad appeal in the stewardship of nanotechnology and its acceptance by the public. This work represents some of the early research in burgeoning field of nanotoxicology. Using a variety of in vivo and in vitro models, as well as cellular and molecular techniques I first studied a possible role for the novel cytokine endothelial monocyte activating polypeptide-II (EMAP-II) in acute lung inflammation in rats (Chapter 2). This work demonstrated a significant increase in total EMAP-II concentration in lipopolysaccharide inflamed lungs as early as 1h post-treatment (P<0.05). Increased numbers of monocytes and granulocytes were also observed in lungs treated with mature EMAP-II relative to control rats (P<0.05), and the recruitment of cells did not occur via upregulation of either Interleukin-1β or Macrophage inflammatory protein-2. I further studied whether mature EMAP-II can be induced in pulmonary nanotoxicity studies by exposure to rosette nanotubes (RNT) (Chapters 3-5). In the first in vivo experiments in mice on the RNT(1)-G0 (Chapter 3) I showed an acute inflammatory response at the 50 µg dose by 24h, but this response was resolving by 7d post-exposure as evidenced by a decreased number of cells in the bronchoalveolar lavage fluid (P<0.05) and from histological examination. The results of this study indicated that water soluble and metal-free rosette nanotubes can demonstrate a favorable acute pulmonary toxicity profile in mice. Subsequently, I studied the responses of the pulmonary epithelium using the human Calu-3 cell line (Chapter 4). This experiment indicated that RNT(2)-K1 neither reduces cell viability at 1 or 5 µg/ml doses nor does it induce a dose-dependent inflammatory cytokine response in pulmonary epithelial cells in vitro. My final experiment (Chapter 5) studied the human U937 pulmonary macrophage cell line since the macrophage is one of the key defense mechanisms to encounter RNT in the lung environment. The data indicate that this cell line lacks a robust inflammatory response upon exposure to RNT and that when RNT length is changed by altering the conditions of nanotube self-assembly, cytokine release into the supernatant is not affected profoundly. Although, EMAP-II is upregulated in a lipopolysaccharide model of lung inflammation, it does not serve as a good marker of RNT exposure. The data indicate that RNT have a favourable toxicity profile and these experiments provide a framework upon which rosette nanotubes can be investigated for a range of biomedical applications. Furthermore, in light of media and scientific reports of nanomaterials showing signs of toxicity, this work demonstrates that a biologically inspired nanostructure such as the RNT can be introduced to physiological environments without acute toxicity.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:SSU.etd-12042007-201921 |
| Date | 06 December 2007 |
| Creators | Journeay, William Shane |
| Contributors | Sharma, Rajendra K., Misra, Vikram, Koehncke, Niels, Chan, Warren, Blakley, Barry R., Singh, Baljit |
| Publisher | University of Saskatchewan |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-12042007-201921/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Saskatchewan or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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