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Abstract
Rationale: Exposure of the lung to ionizing radiation, such as during radiotherapy, can result in pulmonary fibrosis (PF), which has few treatment options. PF is characterized by an accumulation of extracellular matrix proteins that form scar tissue, resulting in dyspnea, disruption of gas exchange, and even death. We and others have shown that metabolic reprogramming is a hallmark of idiopathic pulmonary fibrosis (IPF). IPF lung tissue, and lung fibroblasts treated with TGF-β, exhibit increased aerobic glycolysis with increased expression of lactate dehydrogenase A (LDHA) and excess production of lactate, leading to reduced extracellular pH that activates latent TGF-β. Here, we hypothesized that ionizing radiation would cause aerobic glycolytic metabolic dysregulation in primary human lung fibroblasts.
Results: Primary non-fibrotic HLFs exposed to irradiation exhibited significant upregulation of Pyruvate Dehydrogenase Kinase (PDK1 (0.5 – 3-fold, p<0.05) and LDHA (1.4-fold, p<0.05). Cell viability was unaffected by increased radiation dose.
Conclusions: Radiation increased fibroblast expression of genes involved in fibrotic phenotypes (αSMA) and aerobic glycolysis (PDK1 and LDHA), in a similar pattern to that seen in IPF fibroblasts. The metabolic changes are closely associated with creating a profibrotic extracellular environment in IPF by promoting an acidic environment. Our evidence suggests this phenomenon can be driven by radiation in lung fibroblasts and affirm that glycolytic reprogramming may also be a hallmark of radiation-induced fibrosis. Further understanding of the common mechanisms that create this metabolic shift could provide novel therapeutics for fibrosis treatment.
Publication Date
2021
Keywords
radiation, metabolism, fibrosis, pulmonary
Disciplines
Biological Phenomena, Cell Phenomena, and Immunity | Medical Molecular Biology
Faculty Advisor/Mentor
Patricia J. Sime
Is Part Of
VCU Graduate Research Posters
Included in
Biological Phenomena, Cell Phenomena, and Immunity Commons, Medical Molecular Biology Commons