Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway
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 secret...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Critical Care |
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| Online Access: | https://doi.org/10.1186/s13054-023-04488-5 |
| _version_ | 1797818018827337728 |
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| author | Peng Ding Rui Yang Cheng Li Hai-Long Fu Guang-Li Ren Pei Wang Dong-Yu Zheng Wei Chen Li-Ye Yang Yan-Fei Mao Hong-Bin Yuan Yong-Hua Li |
| author_facet | Peng Ding Rui Yang Cheng Li Hai-Long Fu Guang-Li Ren Pei Wang Dong-Yu Zheng Wei Chen Li-Ye Yang Yan-Fei Mao Hong-Bin Yuan Yong-Hua Li |
| author_sort | Peng Ding |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T09:02:03Z |
| format | Article |
| id | doaj.art-d02cc50382c54d59a2a568359510a364 |
| institution | Directory Open Access Journal |
| issn | 1364-8535 |
| language | English |
| last_indexed | 2024-03-13T09:02:03Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Critical Care |
| spelling | doaj.art-d02cc50382c54d59a2a568359510a3642023-05-28T11:18:00ZengBMCCritical Care1364-85352023-05-0127111510.1186/s13054-023-04488-5Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathwayPeng Ding0Rui Yang1Cheng Li2Hai-Long Fu3Guang-Li Ren4Pei Wang5Dong-Yu Zheng6Wei Chen7Li-Ye Yang8Yan-Fei Mao9Hong-Bin Yuan10Yong-Hua Li11Department of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical UniversityDepartment of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical UniversityDepartment of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical UniversityDepartment of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical UniversityDepartment of Anesthesiology, PLA No.983 HospitalDepartment of Pharmacology, College of Pharmacy, Naval Medical UniversityDepartment of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical UniversityDepartment of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical UniversityDepartment of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical UniversityDepartment of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineDepartment of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical UniversityDepartment of Anesthesiology, Changzheng Hospital, The Second Affiliated Hospital of Naval Medical UniversityAbstract 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.https://doi.org/10.1186/s13054-023-04488-5Ventilator-induced lung injuryFibroblast growth factor 21PyroptosisNLRP3Caspase-1Gasdermin D |
| spellingShingle | Peng Ding Rui Yang Cheng Li Hai-Long Fu Guang-Li Ren Pei Wang Dong-Yu Zheng Wei Chen Li-Ye Yang Yan-Fei Mao Hong-Bin Yuan Yong-Hua Li Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway Critical Care Ventilator-induced lung injury Fibroblast growth factor 21 Pyroptosis NLRP3 Caspase-1 Gasdermin D |
| title | Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway |
| title_full | Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway |
| title_fullStr | Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway |
| title_full_unstemmed | Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway |
| title_short | Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway |
| title_sort | fibroblast growth factor 21 attenuates ventilator induced lung injury by inhibiting the nlrp3 caspase 1 gsdmd pyroptotic pathway |
| topic | Ventilator-induced lung injury Fibroblast growth factor 21 Pyroptosis NLRP3 Caspase-1 Gasdermin D |
| url | https://doi.org/10.1186/s13054-023-04488-5 |
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