The Regulation of IL-33 and Arginase-1 by Oncostatin M in Mouse Lung Systems
| Autor: | Dubey, Anisha |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: | |
| Druh dokumentu: | Diplomová práce |
| Popis: | Excessive tissue fibrosis in various lung diseases contributes to decline in lung function and subsequent morbidity and mortality. Mechanisms involve complex networks of molecules such as cytokines that are not clearly worked out in conditions such as Idiopathic pulmonary fibrosis (IPF). Furthermore, pulmonary virus infection has been linked to exacerbations of IPF. Previous studies have demonstrated that transient pulmonary over-expression of Oncostatin M (OSM) leads to increased extracellular matrix (ECM) accumulation, Th2-skewed cytokines and Arg1+ M2-like macrophage accumulation in mouse models. OSM can also robustly induce interleukin-33 (IL-33), an IL1 family cytokine or alarmin, both in vivo and in vitro mouse lung systems. Since others have shown that soluble IL-33 exacerbates bleomycin-induced lung fibrosis in mouse models and is associated with Th2-type lung diseases, IL-33 may mediate OSM effects on ECM and Arg1+ macrophage-like cell accumulation. The main hypothesis in this thesis is that OSM can induce IL-33 expression and Arg1+ cells, that OSM can potentiate IL-33 release from virally-infected epithelial cells, and that OSM can prime lungs to subsequent influenza infection and exacerbate pathology. Results demonstrated that OSM induced robust up-regulation of pulmonary IL-33 and Arg1 mRNA and protein expression in vivo, in comparison to another gp130 cytokine, IL-6. However, IL-6 was required for OSM-induced arginase-1 expression in vivo, but not IL-33 expression in vivo. OSM-induced Arg1 expression was also dependent upon IL-33 presence as demonstrated in IL-33-/- animals. This finding implicates a role for both IL-33 and IL-6 in mediating OSM-induced Arg1+ macrophage-like cell accumulation within the lung. Additionally, results showed that a respiratory Influenza A virus infection in vivo alone induced a time-dependent increase in OSM and IL-33 (Day 4), however reduced IL-33 by 7-days post-infection. Influenza infection in AdOSM-primed mice and led to decreased IL-33 expression and eosinophilic infiltration within the lung 5-days post-influenza infection. Collectively, these results demonstrate that OSM can drive Th2-associated pathology correlated to increased IL-33 and Arg1 expression. Contrary to expectations, influenza A virus infection led to a reduction in OSM-induced Th2-phenotype in vivo. Further exploration into the OSM-IL-33 pathway will provide insight into innate immune mechanisms of lung inflammation, virus infection and control of ECM accumulation. Thesis Master of Science (MSc) |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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