UC Davis

This dissertation focuses on discussing how metabolic reprogramming shapes pulmonary fibrosis, particularly idiopathic pulmonary fibrosis (IPF). IPF is a detrimental interstitial lung disease with an unfavorable outcome. Although the etiology remains unknown, cigarette smoking has been considered as a risk factor for IPF. Previous findings have found that smoking can alter metabolic regulation in inflammatory lung diseases, including COPD, asthma and IPF. Metabolomics has been a powerful tool to identify putative biomarkers and novel signaling mechanisms in disease research. Untargeted metabolomics approach was used in our study to profile cellular metabolic changes in primary lung fibroblasts derived from normal and IPF patients. IPF lung fibroblasts displayed a different metabolic landscape as compared to normal lung fibroblasts, in which arginine-related metabolic pathways were significantly altered due to the absence of argininosuccinate synthase (ASS1) expression in IPF lung fibroblasts. Removing arginine from cell culture and media was specific to IPF lung fibroblast and pulmonary fibrosis. Because of the critical function of arginine metabolism in lung fibroblasts, ASS1 expression was knocked down in normal lung fibroblasts to examine the changes in metabolic pathways. Myo-inositol metabolism was found to be significantly disturbed in ASS1-deficient lung fibroblasts. Myo-inositol treatment demonstrated in vivo and in vitro antifibrotic effects. Overall, our studies have demonstrated the pivotal role of amino acid metabolism in IPF lung fibroblasts.