HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis.

AbstractRATIONALE:
Dysregulation of cellular metabolism has been shown to participate in several pathologic processes. However, the role of metabolic reprogramming is not well appreciated in the pathogenesis of organ fibrosis.
OBJECTIVES:
To determine if glycolytic reprogramming participates in the pathogenesis of lung fibrosis and assess the therapeutic potential of glycolytic inhibition in treating lung fibrosis.
METHODS:
A cell metabolism assay was performed to determine glycolytic flux and mitochondrial respiration. Lactate levels were measured to assess glycolysis in fibroblasts and lungs. Glycolytic inhibition by genetic and pharmacologic approaches was used to demonstrate the critical role of glycolysis in lung fibrosis.
MEASUREMENTS AND MAIN RESULTS:
Augmentation of glycolysis is an early and sustained event during myofibroblast differentiation, which is dependent on the increased expression of critical glycolytic enzymes, in particular, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Augmented glycolysis contributes to the stabilization of hypoxia-inducible factor 1-α, a master regulator of glycolytic enzymes implicated in organ fibrosis, by increasing cellular levels of tricarboxylic acid cycle intermediate succinate in lung myofibroblasts. Inhibition of glycolysis by the PFKFB3 inhibitor 3PO or genomic disruption of the PFKFB3 gene blunted the differentiation of lung fibroblasts into myofibroblasts, and attenuated profibrotic phenotypes in myofibroblasts isolated from the lungs of patients with idiopathic pulmonary fibrosis. Inhibition of glycolysis by 3PO demonstrates therapeutic benefit in bleomycin-induced and transforming growth factor-β1-induced lung fibrosis in mice.
CONCLUSIONS:
Our data support the novel concept of glycolytic reprogramming in the pathogenesis of lung fibrosis and provide proof-of-concept that targeting this pathway may be efficacious in treating fibrotic disorders, such as idiopathic pulmonary fibrosis.
AuthorsNa Xie, Zheng Tan, Sami Banerjee, Huachun Cui, Jing Ge, Rui-Ming Liu, Karen Bernard, Victor J Thannickal, Gang Liu
JournalAmerican journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 192 Issue 12 Pg. 1462-74 (Dec 15 2015) ISSN: 1535-4970 [Electronic] United States
PMID26284610 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Topics
  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Disease Models, Animal
  • Glycolysis (physiology)
  • Humans
  • Idiopathic Pulmonary Fibrosis (metabolism, physiopathology)
  • Lung (metabolism, physiopathology)
  • Mice
  • Mice, Inbred C57BL
  • Myofibroblasts (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: