期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 58, 期 2, 页码 216-231出版社
AMER THORACIC SOC
DOI: 10.1165/rcmb.2016-0186OC
关键词
fibroblasts; hypoxia inducible factor-1 alpha; pulmonary fibrosis; pyruvate dehydrogenase kinase1; dichloroacetate
资金
- Pulmonary Fibrosis Foundation [310063]
- National Institutes of Health (NIH) [R21 CA208746]
- Welch Foundation [AT-1595]
- American Heart Association [SDG 33400239]
- NIH [R01 CA163649, R01 CA210439, R01 CA216853]
- SPORE [2P50 CA127297]
- Ministry of Health and Welfare of Republic of Korea [HI16C1501]
- Sylvester Comprehensive Cancer Center funding
- Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology [JPMJPR14M4]
- [26111003]
- NATIONAL CANCER INSTITUTE [R01CA210439, R21CA208746, R01CA163649, P50CA127297, R01CA216853] Funding Source: NIH RePORTER
Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences, such as hypoxia, contribute to their sustained activation and differentiation is poorly understood. As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the preclinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis. Bleomycin-induced pulmonary fibrotic progression was evaluated in two independent, fibroblast-specific, promoter-driven, hypoxia-inducible factor (Hif) 1A knockout mouse models and in glycolytic inhibitor, dichloroacetate-treated mice. Genetic and pharmacological approaches were used to explicate the role of metabolic reprogramming in myofibroblast differentiation. Hypoxia significantly enhanced transforming growth factor-beta-induced myofibroblast differentiation through HIF-1 alpha, whereas overexpression of the critical HIF-1 alpha-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1 alpha. Inhibition of the HIF-1 alpha/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1 alpha/PDK1-mediated glycolytic reprogramming is a critical metabolic alteration that acts to promote myofibroblast differentiation and fibrotic progression, and demonstrate that targeting glycolytic metabolism may prove to be a potential therapeutic strategy for the treatment of pulmonary fibrosis.
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