Azuelos, Ilan;
(2020)
Glucose metabolism in idiopathic pulmonary fibrosis.
Doctoral thesis (M.D(Res)), UCL (University College London).
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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.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | M.D(Res) |
| Title: | Glucose metabolism in idiopathic pulmonary fibrosis |
| Event: | UCL |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10091826 |
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