期刊
THERANOSTICS
卷 12, 期 14, 页码 6057-6068出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.72328
关键词
integrin beta 3; pyruvate kinase M2; aerobic glycolysis; mechanical ventilation; pulmonary fibrosis
资金
- National Natural Science Foundation of China (NSFC) [81870052]
- Shanghai Municipal Health Commission of China [20204Y0290]
This study found that the integrin beta 3-PKM2 pathway-mediated aerobic glycolysis is involved in mechanical ventilation-induced pulmonary fibrosis. Inhibiting aerobic glycolysis targeting the integrin beta 3-PKM2 pathway may be a promising treatment for mechanical ventilation-induced pulmonary fibrosis.
Background: Mechanical ventilation (MV) can induce pulmonary fibrosis. This study aims to investigate whether MV-induced pulmonary fibrosis is associated with aerobic glycolysis and seeks to uncover the underlying mechanisms mediated by integrin beta 3-pyruvate kinase M2 (PKM2) pathway. Methods: PKM2 knockdown or inhibition, integrin beta 3 knockout or inhibition and wild-type mice were exposed to MV (20 mL/kg) for 2 h. Results: Mice exposed to MV exhibited increased expression of collagen deposition, and upregulation of a-smooth muscle actin and collagen I in lung tissues. Single cells analysis showed that MV-induced pulmonary fibrosis was associated with increased gene expression of integrin and glycolysis in pulmonary fibroblasts, as well as upregulation of glycolytic products tested by metabolomics. Meanwhile, increased protein level of integrin beta 3 and PKM2 was confirmed by western blot and immunohistochemistry. Double immunofluorescence staining and flow cytometric analysis showed increased number of fibronectin+/integrin beta 3+ and fibronectin+/PKM2+ fibroblasts in lung tissues. Furthermore, MV-induced aerobic glycolysis and pulmonary fibrosis were ameliorated after treatment with PKM2 knockdown-AAV and inhibition, or in integrin beta 3 knockout and inhibition mice. Conclusions: Integrin beta 3-PKM2 pathway-mediated aerobic glycolysis contributes to MV-induced pulmonary fibrosis. The inhibition of aerobic glycolysis targeting integrin beta 3-PKM2 pathway may be a promising treatment for MV-induced pulmonary fibrosis.
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