2. Academic Validation
  3. Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway

Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway

  • Crit Care. 2023 May 22;27(1):196. doi: 10.1186/s13054-023-04488-5.
Peng Ding # 1 2,  Rui Yang # 1,  Cheng Li # 1,  Hai-Long Fu 1,  Guang-Li Ren 2,  Pei Wang 3,  Dong-Yu Zheng 1,  Wei Chen 1,  Li-Ye Yang 1,  Yan-Fei Mao 4,  Hong-Bin Yuan 5,  Yong-Hua Li 6
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical University, Shanghai, China.
  • 2 Department of Anesthesiology, PLA No.983 Hospital, Tianjin, China.
  • 3 Department of Pharmacology, College of Pharmacy, Naval Medical University, Shanghai, China.
  • 4 Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 5 Department of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical University, Shanghai, China. [email protected].
  • 6 Department of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 37218012 DOI: 10.1186/s13054-023-04488-5
Abstract

Background: Ventilator-induced lung injury (VILI) is caused by overdistension of the alveoli by the repetitive recruitment and derecruitment of alveolar units. This study aims to investigate the potential role and mechanism of Fibroblast Growth Factor 21 (FGF21), a metabolic regulator secreted by the liver, in VILI development.

Methods: Serum FGF21 concentrations were determined in patients undergoing mechanical ventilation during general anesthesia and in a mouse VILI model. Lung injury was compared between FGF21-knockout (KO) mice and wild-type (WT) mice. Recombinant FGF21 was administrated in vivo and in vitro to determine its therapeutic effect.

Results: Serum FGF21 levels in patients and mice with VILI were significantly higher than in those without VILI. Additionally, the increment of serum FGF21 in anesthesia patients was positively correlated with the duration of ventilation. VILI was aggravated in FGF21-KO mice compared with WT mice. Conversely, the administration of FGF21 alleviated VILI in both mouse and cell models. FGF21 reduced Caspase-1 activity, suppressed the mRNA levels of Nlrp3, Asc, Il-1β, IL-18, Hmgb1 and NF-κB, and decreased the protein levels of NLRP3, ASC, IL-1β, IL-18, HMGB1 and the cleaved form of GSDMD.

Conclusions: Our findings reveal that endogenous FGF21 signaling is triggered in response to VILI, which protects against VILI by inhibiting the NLRP3/Caspase-1/GSDMD Pyroptosis pathway. These results suggest that boosting endogenous FGF21 or the administration of recombinant FGF21 could be promising therapeutic strategies for the treatment of VILI during anesthesia or critical care.

Keywords

Caspase-1; Fibroblast growth factor 21; Gasdermin D; NLRP3; Pyroptosis; Ventilator-induced lung injury.

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