The role of Alveolar Epithelial Cell Metabolic Reprogramming in Idiopathic Pulmonary Fibrosis

摘要

Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown cause marked by dysfunctional wound healing and aberrant fibrotic remodeling of the lung that claims the lives of more than 40,000 Americans each year. The median age of IPF is 66 years and patients have an average life expectancy of 3 years. The scientific discovery into this disease has been slow and has resulted in only two FDA approved medications that do not reverse or cure the disease. In light of the increasing longevity of the American population, understanding the underlying drivers of this disease is essential. Recently, the critical role of epithelial biology in the development and progression of this disease has become a high impact question that requires further elucidation. To address this unmet need, we will utilize a novel preclinical murine model (SftpcI73T) of IPF that closely recapitulates many aspects of the human disease and permits temporal modeling of subclinical events in its pathogenesis. Founded in compelling preliminary data, the overall goal of this project is to capitalize on the aforementioned novel Sftpc model to characterize the metabolic dysfunction in epithelial cells and identify potential pathways for pharmacologic intervention. In this model, I have found that the alveolar type II epithelial cell (AT2) undergoes marked changes in metabolism including a shift towards enhanced glycolysis, alterations in TCA cycle intermediates, and changes in mitochondrial dynamics. From this I hypothesize that in IPF an acquired deficiency in AT2 cell quality control initiates a cascade of metabolic reprogramming in the cell that promotes a profibrotic AT2 endophenotype(s) which can initiate, amplify and enhance fibrogenesis. We will test this hypothesis in two specific aims: 1) Using the SftpcI73T mutant, characterize the scope of AT2 metabolic reprogramming in IPF focusing on mitochondrial function, mitochondrial dynamics, and TCA intermediate flux. 2) Determine the effect of altered metabolism on AT2 function during fibrogenesis both in- vitro and in-vivo. The findings from this study will characterize the role of metabolic reprogramming in epithelial dysfunction and elucidate potential targets for therapeutic intervention. Beyond the scope of IPF, epithelial dysfunction is an important aspect of chronic and acute lung disease, particularly in light of the COVID-19 pandemic.