| dc.contributor.author | Weppler, Amy Lynn. | en_US |
| dc.date.accessioned | 2014-10-21T12:38:31Z | |
| dc.date.available | 2007 | |
| dc.date.issued | 2007 | en_US |
| dc.identifier.other | AAINR27187 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/54893 | |
| dc.description | The role of endothelial cells in inflammation is critical as they provide directional signals to leukocytes, including neutrophils, during transmigration. While leukocyte recruitment to inflammatory sites is essential for effective control of inflammation and initiation of repair, uncontrolled leukocyte recruitment can cause significant damage. Leukocyte recruitment must therefore be carefully regulated to achieve a balance between the beneficial and detrimental effects of inflammation. The purpose of this study was to examine the mechanisms involved in neutrophil transendothelial migration following activation of the endothelium by various inflammatory mediators. | en_US |
| dc.description | An in vitro model of the human lung alveolus was developed by systematically evaluating the capacity of various human lung epithelial cell lines to grow adjacent to primary human endothelium on semi-porous membranes. Using an optimized model, it was determined that contact between epithelium and endothelium resulted in decreased neutrophil transmigration across endothelial monolayers in response to bacterial endotoxin, but not in response to the inflammatory cytokine TNF-alpha. Additionally, lung epithelium attenuated the increase in expression of cell adhesion molecules (CAM) on the endothelium in response to endotoxin but not in response to TNF-alpha. The increase in production of the neutrophil chemoattractant, CXCL8 was not modified. Known anti-inflammatory mediators such as IL-10, TNF-beta and nitric oxide were not responsible for the observed decrease in neutrophil migration. Further studies assessed the ability of microbial products to activate endothelium via Toll-like receptor (TLR) activation. Human endothelium expressed TLRI-6 under resting conditions and TLR7 and 9 following activation. Endothelium incubated with microbial agonists of TLR upregulated expression of CAM and production of CXCL8. Finally, various TLR agonists induced neutrophil transendothelial migration that was dependent on CD 18 integrin to varying extents, suggesting that activation of endothelium by different TLR can result in differential involvement of adhesion mechanisms in leukocyte transendothelial migration. The findings of this study demonstrate that alveolar epithelium can selectively modulate endothelial responses to inflammatory stimuli and this alters the ability of neutrophils to migrate across the endothelium. Furthermore, endothelium is activated by a broader range of microbial products than hitherto recognized, which may in part determine the predominant adhesive mechanisms mediating neutrophil transendothelial migration. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 2007. | en_US |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | | en_US |
| dc.subject | Health Sciences, Immunology. | en_US |
| dc.title | Neutrophil-endothelial cell interactions: Modulation by alveolar epithelial cells and Toll-like receptor agonists. | en_US |
| dc.type | text | en_US |
| dc.contributor.degree | Ph.D. | en_US |
