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- W3012600900 abstract "Idiopathic pulmonary fibrosis (IPF) is a life-threatening interstitial lung disease of unknown aetiology characterized by progressive scarring of the lung parenchyma. Histologically, the hallmark of the disease is the presence of interspersed fibroblastic foci in the lung, composed of contractile myofibroblasts synthesizing a dense collagen-rich matrix. Transforming growth factor-β1 (TGFβ1) has been recognized as a key cytokine in the pathophysiology of IPF and other fibrotic disorders. Highly proliferative cells, such as cancer cells, reprogram their glucose metabolism through the activation of the PI3K-AKT-mTOR axis towards enhanced glycolysis, a process known as aerobic glycolysis. In view of the high biosynthetic nature of myofibroblasts, this thesis aimed to (1) describe the changes in glucose metabolism that occur during the process of TGFβ1-induced fibroblast to myofibroblast differentiation, (2) examine whether these changes are regulated by the PI3K-AKT-mTOR axis, and (3) examine the relationship between glucose uptake and fibrogenesis in an experimental model of lung fibrosis. For the in vitro experiments, the metabolic profile of primary human lung fibroblasts was assessed by examining cellular glucose uptake, glycolytic flux and mitochondrial respiration. Furthermore, using highly selective and potent pharmacological inhibitors, the role of the PI3K-AKT-mTOR pathway in promoting changes in glucose metabolism during fibroblast differentiation was examined. For the in vivo experiments, position emission tomography-computed tomography scanning and autoradiography were performed in the murine bleomycin model of lung injury and fibrosis following administration of radioactive 18F-labeled fluoro-2-deoxyglucose. Taken together, the data presented in this thesis demonstrate that the metabolic phenotype of fibroblasts changes during TGFβ1-induced fibroblast differentiation and is regulated by mTOR, in a PI3K-AKT-independent manner. This metabolic switch may further explain the observation of increased glucose uptake in the fibrotic lesions in the bleomycin model of lung fibrosis. These findings support the notion that pharmacological targeting of glucose metabolism and/or the mTOR kinase may be beneficial in preventing myofibroblast differentiation in IPF." @default.
- W3012600900 created "2020-03-27" @default.
- W3012600900 creator A5073420918 @default.
- W3012600900 date "2020-02-28" @default.
- W3012600900 modified "2023-09-23" @default.
- W3012600900 title "Glucose metabolism in idiopathic pulmonary fibrosis" @default.
- W3012600900 hasPublicationYear "2020" @default.
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