Selvarajah, Brintha; (2021) The role of metabolic reprogramming in the pathogenesis of idiopathic pulmonary fibrosis. Doctoral thesis (Ph.D), UCL( University College London).

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease of unknown aetiology. It conveys a poor median survival of 3.5 years, a prognosis worse than many cancers. The pathomechanisms that contribute to IPF are not fully elucidated and treatment options remain limited. Transforming growth factor-β (TGF-β) is a critical pro-fibrotic cytokine that drives fibroblast to myofibroblast differentiation resulting in excessive collagen deposition in the lung parenchyma. Subsequent distortion of the lung architecture leads to respiratory failure and ultimately death. Metabolic reprogramming underlies many diseases including cancer and akin to cancer, enhanced 18F-FDG-PET has recently been observed in IPF patients, suggesting altered glucose metabolism may also be a feature of IPF pathology. There is emerging evidence that alterations in the metabolism of myofibroblasts may be critical in fibroproliferative pathobiology. Recent work from our laboratory has shown that activation of the mTOR axis, a key metabolic regulator, is critical for regulating myofibroblast collagen synthesis. This thesis identifies that TGF-β1 enhances the production of activating transcription factor 4 (ATF4), the transcriptional master regulator of amino acid metabolism, to supply glucose-derived glycine to meet the amino acid requirements associated with enhanced collagen production in response to myofibroblast differentiation. Dissection of signalling pathways involved show that TGF-β1 induced ATF4 production depends on the cooperation between canonical TGF-β1 signalling through Smad3 and activation of mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). ATF4, in turn promotes the transcription of genes encoding enzymes of the de novo serine-glycine biosynthetic pathway and glucose transporter 1 (GLUT1). Taken together, this work identifies the TGF-β1-mTORC1-ATF4 axis as a potential novel therapeutic target pathway for interfering with myofibroblast function in fibrosis.

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