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Title: | Oncostatin M Regulation of Airway Smooth Muscle Cells and its Expression by Blood Mononuclear Cells |
Authors: | Kwofie, Karen |
Advisor: | Richards, Carl D |
Department: | Medical Sciences |
Publication Date: | Nov-2014 |
Abstract: | Asthma is a complex respiratory condition that has markedly increased in prevalence over the past 5 decades. It is classified as a chronic inflammatory disease of the airways due to overzealous immunological pathways resulting in increased immune cell infiltration, changes in the extracellular matrix/airway structural integrity and airway hyper-responsiveness. Commonly, persons with asthma experience exacerbations associated with bacterial and/or viral infections that significantly increase the morbidity and rate of hospitalization of individuals with this condition. The mechanisms that cause these exacerbations are not yet clear. It is postulated here that Oncostatin M (OSM) is released by macrophage cells in response to viral/bacterial products and contributes to the pathology in exacerbations through stimulating human airway smooth muscle cell (HASMC) pro-inflammatory responses, modulation of extracellular matrix (ECM) protein expression and HASMC proliferation. The findings of this thesis showed that OSM indeed could stimulate HASMC production of various cytokines including: IL-6, monocyte chemotactic protein (MCP)-1, MCP-3, Eotaxin-1, Eotaxin-3, IL-8 and vascular endothelial growth factor (VEGF). Furthermore, OSM could act in a synergistic manner with IL-4, IL-13 or IL-17A in the selective expression of: IL-6, MCP-1, Eotaxin-1, Eotaxin-3, IL-8 and VEGF by cultured HASMC. Elevation in MCP-1 and IL-6 expression was sensitive to p38 and STAT inhibition indicating the engagement of these signalling pathways. OSM did not consistently modulate changes in ECM remodelling proteins or proliferation of these cells in vitro. The findings also demonstrate that toll-like receptor (TLR)-4 and TLR-7/8 ligands could markedly elevate OSM steady state mRNA and protein expression in cultured peripheral blood mononuclear cells (PBMC) that were differentiated towards macrophages with M-CSF but not in the absence of M-CSF. Collectively, these in vitro results suggest a mechanism for viral/bacterial-induced asthma exacerbations that involves elevated OSM production by infiltrating monocytes in response to these pathogens and subsequent augmentation of HASMC pro-inflammatory responses and synergistic expression of select chemotactic factors resulting in acute asthma exacerbations. |
URI: | http://hdl.handle.net/11375/16493 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Kwofie_Karen_201411_MSc.pdf | 2.63 MB | Adobe PDF | View/Open |
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