Department of Thoracic Surgery, Ganzhou Hospital of Guangdong Provincial People's Hospital, Ganzhou Municipal Hospital, Ganzhou 341009, Jiangxi, China.
Department of Cardiology, Ganzhou Hospital of Guangdong Provincial People's Hospital, Ganzhou Municipal Hospital, Ganzhou 341009, Jiangxi, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 1):113307. doi: 10.1016/j.intimp.2024.113307. Epub 2024 Oct 3.
Acute lung injury is a critical life-threatening complication of pulmonary and cardiac surgery with a high rate of morbidity and mortality. Fibroblast growth factor 21 (FGF21) has been reported to play an important role in protecting vital organs from damage. This study aims to investigate the potential protective role and mechanism of FGF21 in pulmonary ischemia/reperfusion (I/R)-induced acute lung injury.
A pulmonary epithelial cell line was treated with hypoxia/regeneration (H/R) in vitro and a mouse model of acute lung injury was induced with pulmonary I/R in vivo. Lung injury after pulmonary I/R was compared between FGF21-konckout (KO) mice and wild-type (WT) mice. Recombinant FGF21 was administrated in vivo and in vitro to determine its therapeutic effect.
Circulating levels of FGF21 in mice with pulmonary I/R injury were significantly higher than in those without pulmonary I/R injury. Lung injury was aggravated in FGF21-KO mice compared with WT mice and the administration of FGF21 alleviated lung injury in mouse treated with I/R and pulmonary epithelial cell injury treated with H/R. FGF21 treatment decreased endoplasmic reticulum (ER) stress, Fe and lipid reactive oxygen species (ROS) contents and GPX4 expression and increased PTGS2 levels. Mechanistically, FGF21 upregulated the expression of FGFR1 and PPARδ, ameliorated ER stress and ER stress induced-ferroptosis. Furthermore, FGF21 increased the expression level of PPARδ in pulmonary epithelial cell exposed to H/R, which was inhibited by FGFR1 inhibitor (PD173074). The protective effects of FGF21 were abolished by co-treatment with PPARδ inhibitor (GSK0660), indicating FGF21 attenuated ER stress-induced ferroptosis by dependent on FGFR1/PPARδ signaling pathway.
Our study reveals that FGF21 protects against pulmonary I/R injury via inhibiting ER stress-induced ferroptosis though FGFR1/PPARδ signaling pathway. Boosting endogenous FGF21 or the administration of recombinant FGF21 could be promising therapeutic strategies for pulmonary IRI.
急性肺损伤是肺部和心脏手术后危及生命的严重并发症，发病率和死亡率都很高。成纤维细胞生长因子 21（FGF21）已被报道在保护重要器官免受损伤方面发挥重要作用。本研究旨在探讨 FGF21 在肺缺血/再灌注（I/R）诱导的急性肺损伤中的潜在保护作用及其机制。
体外采用低氧/复氧（H/R）处理肺上皮细胞系，体内采用肺 I/R 诱导急性肺损伤模型。比较 FGF21 敲除（KO）小鼠和野生型（WT）小鼠肺 I/R 后的肺损伤。体内和体外给予重组 FGF21 以确定其治疗效果。
肺 I/R 损伤小鼠循环 FGF21 水平明显高于无肺 I/R 损伤小鼠。与 WT 小鼠相比，FGF21-KO 小鼠的肺损伤加重，而给予 FGF21 可减轻 I/R 治疗的小鼠和 H/R 治疗的肺上皮细胞损伤的肺损伤。FGF21 治疗可降低内质网（ER）应激、铁和脂质活性氧（ROS）含量及 GPX4 表达，增加 PTGS2 水平。机制上，FGF21 上调 FGFR1 和 PPARδ 的表达，改善 ER 应激和 ER 应激诱导的铁死亡。此外，FGF21 增加了暴露于 H/R 的肺上皮细胞中 PPARδ 的表达水平，该作用被 FGFR1 抑制剂（PD173074）抑制。FGF21 的保护作用被 PPARδ 抑制剂（GSK0660）共同处理所消除，表明 FGF21 通过 FGFR1/PPARδ 信号通路减轻 ER 应激诱导的铁死亡。
本研究揭示了 FGF21 通过 FGFR1/PPARδ 信号通路抑制 ER 应激诱导的铁死亡来保护肺 I/R 损伤。增强内源性 FGF21 或给予重组 FGF21 可能是肺 IRI 的有前途的治疗策略。
