Idiopathic pulmonary fibrosis (IPF) is one of the most pernicious forms of lung fibrogenesis and currently has very limited effective treatments. Whereas the etiology of IPF remains enigmatic, myofibroblasts (myo-Fbs) have been recognized as effector in the fibrotic pathology. It has become increasingly clear that aerobic glycolysis plays a critical role in supporting the anabolic requirements associated with cancer cell growth and proliferation. However, the role of aerobic glycolysis, the associated serine/glycine metabolism and the TCA cycle alterations in tissue fibrosis has not been examined. In our preliminary studies, we found that lung myo-Fbs and fibrotic human and mouse lungs have augmented aerobic glycolysis. This was likely due to the increased expression of PFKBP3, PFK1, and HK2. We found that PHGDH, the first enzyme that catalyzes the diversion of glycolytic flux to serine/glycine synthesis, is upregulated in lung myo-Fbs and participates in the myo-Fb differentiation. We found that lysine succinylation in Smad2 is increased in lung myo-Fbs, which was presumably caused by an increase in the TCA cycle intermediate succinate and a decrease in desuccinylase Sirt5 expression in these cells. We found that succinate upregulated by augmented glycolysis in lung myo-Fbs stabilizes HIF-1?. We further discovered that HIF-1? is required for myo-Fb differentiation and directly binds to the SMA-? promoter. Most importantly, we found that inhibition of glycolysis diminishes the characteristic phenotypes of lung myo-Fbs in vitro and bleomycin and TGF-?1 induced lung fibrosis in vivo. In this project, we aim to determine the role of aerobic glycolysis in the establishment and sustainment of the myofibroblastic phenotypes; determine the mechanisms by which aerobic glycolysis regulates the myofibroblastic phenotypes of lung myo-Fbs; and determine the therapeutic effects of glycolytic inhibition in mouse models of lung fibrosis.
We aim to determine the role of aerobic glycolysis in the establishment and sustainment of the myofibroblastic phenotypes and lung fibrosis. The studies proposed in this application should not only improve understanding of the roles of aerobic glycolysis in the pathogenesis of lung fibrosis, but also are likely to suggest glycolytic inhibitin being a novel therapeutic approach aimed at decreasing the severity of lung fibrosis.
|Ge, Jing; Cui, Huachun; Xie, Na et al. (2018) Glutaminolysis Promotes Collagen Translation and Stability via ?-Ketoglutarate-mediated mTOR Activation and Proline Hydroxylation. Am J Respir Cell Mol Biol 58:378-390|
|Cui, Huachun; Ge, Jing; Xie, Na et al. (2017) miR-34a promotes fibrosis in aged lungs by inducing alveolarepithelial dysfunctions. Am J Physiol Lung Cell Mol Physiol 312:L415-L424|
|Cui, Huachun; Ge, Jing; Xie, Na et al. (2017) miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence. Am J Respir Cell Mol Biol 56:168-178|
|Xie, Na; Cui, Huachun; Ge, Jing et al. (2017) Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis. Am J Physiol Lung Cell Mol Physiol 313:L834-L844|
|Cui, Huachun; Banerjee, Sami; Xie, Na et al. (2016) MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation. Am J Respir Cell Mol Biol 54:843-52|