LSC - 2017 - Targeting glucose metabolism in experimental lung injury and fibrosis

Introduction: Akin to many cancers, enhanced18F-FDG-PET signal has been associated with fibrotic lesions in pulmonary fibrosis. In tumors, elevated glucose uptake is indicative of a metabolic switch to aerobic glycolysis (AG), critical to fuel biosynthetic demand. De novo expression of the low-activity isoform of the ‘glycolytic gatekeeper’ pyruvate kinase, PKM2, is a key driver of AG and pharmacological modulation of PKM2 is known to attenuate tumor proliferation and tumorigenesis. Aim: We hypothesised that the fibroproliferative response to bleomycin lung injury is characterised by metabolic reprogramming driving an enhanced glucose requirement of cells in the injured lesions. We investigated glucose uptake and modulation of the glycolytic marker PKM2 in the bleomycin mouse model. Methodsu0026Results: Autoradiography of18F-FDG uptake in cryofrozen lung sections at day 28 post-bleomycin showed a significant ›50% increase in18F-FDG uptake in bleomycin-challenged compared to uninjured lungs. The regions of highest18F-FDG uptake corresponded to dense fibrotic regions. Immunohistochemistry revealed that PKM2 was localised to multiple cell types in fibrotic lung lesions, including a-SMA-positive myofibroblasts. A small molecule activator of PKM2, TEPP-46, achieved a significant ~50% increase in PKM2 activity in the bleomycin-injured lung. However, chronic TEPP-46 administration from day 5 post-injury had no significant effect on lung fibrosis quantified by microCt at day 28. Conclusions: We show that glucose uptake is significantly increased in fibrotic lung lesions. Although fibrotic lesions express PKM2, increasing the activity of this isoform was not sufficient to influence progression of fibrosis in bleomycin lung injury