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Title: | The Role of the Oncostatin M-STAT6 Axis in Pulmonary Eosinophilia, Goblet Cell Hyperplasia, Airway Hyperresponsiveness and Pulmonary Fibrosis |
Authors: | Fritz, Dominik K. |
Advisor: | Richards, Carl D. |
Department: | Medical Sciences |
Publication Date: | Feb-2010 |
Abstract: | <p>Various mediators including cytokines control and modulate inflammatory responses in tissues and organs that incorporate cell infiltration, accumulation and extracellular matrix remodeling. Oncostatin M (OSM), a pleiotropic and multifunctional cytokine of the gp130 cytokine family, has been shown to be upregulated in allergic and fibrotic airway disease conditions associated with tissue eosinophilic inflammation. In an in vivo model of airway disease, previous work has shown that transient overexpression of OSM in mouse lungs elicits marked pulmonary eosinophilic inflammation and interstitial pulmonary fibrosis implicating OSM in pulmonary eosinophilic diseases. Among the gp130 cytokine family members, OSM has been established to exhibit unique and/or potent connective tissue responses in vitro and in vivo, which may be of important consequence in pulmonary disease conditions. This thesis provides experimental work that examines the mechanism of OSM induced fibroblast cell responses in vitro, and further examines mechanisms of OSM function in an in vivo model of airway disease. The research presented identifies OSM as a unique gp 130 cytokine family member in regulation of the STAT6 signaling/transcription factor, which was originally characterized as a signaling pathway activated downstream of the IL-4 receptor (IL-4R) by the TH2 cytokines IL-4 and IL-13. This novel finding provided a foundation for subsequent studies, which examined the role of STAT6 in the regulation of OSM-induced connective tissue responses in the context of pulmonary inflammation. Migration of eosinophils from circulation and into inflamed lungs is orchestrated by the upregulation of adhesion molecules (VCAM-1) and the establishment of an eosinophil-selective chemotactic gradient ( eotaxins ). It is demonstrated here that OSM potently induces VCAM-1 upregulation and enhances IL-4/IL-13-induced eotaxin-1 expression in lung fibroblasts in comparison to other gp130 cytokines. The STAT6 signaling/transcription factor was found dispensable for VCAM-1 induction, but not for enhanced eotaxin-1 responses. Oncostatin M was also found to be a unique and potent gp130 cytokine in stimulating IL-4R expression in lung fibroblasts in a STAT6 independent fashion, which correlated with enhanced IL- 4/IL-13-induced eotaxin-1 production and STAT6 activation. These experimental findings indicated that OSM can sensitize lung structural cells to IL-4/IL-13- induced responses, which could mediate sustained pulmonary eosinophilic inflammation in vivo. In examining mouse lungs in vivo, transient overexpression of OSM induced a T H2-biased inflammatory profile characterized by T H2 cytokine (IL-4, IL-5, IL-13), IL-4R and chemokine (eotaxin-1/2, MCP-1, KC) expression as well as sustained eosinophilic inflammation, mucous/goblet cell hyperplasia, pronounced interstitial extracellular matrix (collagen, a SMA) deposition and airway hyperresponsiveness (AHR). Induction of T H2 cytokines (IL-4, IL-13) and chemokines (eotaxin-112, MCP-1), pulmonary eosinophilia, mucous production and AHR were dependent on STAT6, however induction of IL-4R and interstitial pulmonary extracellular matrix deposition was not. Therefore, this experimental work demonstrates that OSM regulates STAT6-dependent and -independent inflammatory mechanisms that may be important in the control of both allergic and interstitial fibrotic disease processes in the lung.</p> |
Description: | Title: The Role of the Oncostatin M-STAT6 Axis in Pulmonary Eosinophilia, Goblet Cell Hyperplasia, Airway Hyperresponsiveness and Pulmonary Fibrosis, Author: Dominik K. Fritz, Location: Mills |
URI: | http://hdl.handle.net/11375/19458 |
Appears in Collections: | Open Access Dissertations and Theses |
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Fritz_Dominik_K_2010_02_phd.pdf | Title: The Role of the Oncostatin M-STAT6 Axis in Pulmonary Eosinophilia, Goblet Cell Hyperplasia, Airway Hyperresponsiveness and Pulmonary Fibrosis, Author: Dominik K. Fritz, Location: Mills | 17.3 MB | Adobe PDF | View/Open |
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