Journal Article

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

Chen, Wei, Li, Cheng, Zheng, Dong-Yu, Ding, Peng, Yang, Li-Ye, Yang, Rui, Yuan, Hong-Bin, Ren, Guang-Li, Wang, Pei, Li, Yong-Hua, Fu, Hai-Long, Mao, Yan-Fei

2023

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Animals / Artificial respiration / Care and treatment / Caspase 1 - metabolism / Caspase-1 / Catheters / Cell culture / Cell death / Complications and side effects / Critical care / Critical Care Medicine / Cytotoxicity / Demographic aspects / Diabetes / Diagnosis / Disease Models, Animal / Emergency Medicine / Experiments / Fibroblast growth factor 21 / Fibroblast growth factors / Fibroblasts / Gasdermin D / General anesthesia / Growth factors / Health aspects / HMGB1 Protein / Homeostasis / Humans / Inflammasomes / Intensive / Interleukin-18 / Intubation / Kidneys / Laboratory animals / Lavage / Medical research / Medicine / Medicine & Public Health / Metabolism / Mice / Mortality / NLR Family, Pyrin Domain-Containing 3 Protein - genetics / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / NLRP3 / Patients / Pyroptosis / Respiratory tract diseases / Stress measurement / Ventilator-induced lung injury / Ventilator-Induced Lung Injury - drug therapy / Ventilator-Induced Lung Injury - prevention & control / Ventilators