Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage
Uridine metabolism is extensively reported to be involved in combating oxidative stress. Redox-imbalance-mediated ferroptosis plays a pivotal role in sepsis-induced acute lung injury (ALI). This study aims to explore the role of uridine metabolism in sepsis-induced ALI and the regulatory mechanism o...
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| Format: | Article |
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/6/5093 |
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| author | Kai Lai Congkuan Song Minglang Gao Yu Deng Zilong Lu Ning Li Qing Geng |
| author_facet | Kai Lai Congkuan Song Minglang Gao Yu Deng Zilong Lu Ning Li Qing Geng |
| author_sort | Kai Lai |
| collection | DOAJ |
| description | Uridine metabolism is extensively reported to be involved in combating oxidative stress. Redox-imbalance-mediated ferroptosis plays a pivotal role in sepsis-induced acute lung injury (ALI). This study aims to explore the role of uridine metabolism in sepsis-induced ALI and the regulatory mechanism of uridine in ferroptosis. The Gene Expression Omnibus (GEO) datasets including lung tissues in lipopolysaccharides (LPS) -induced ALI model or human blood sample of sepsis were collected. In vivo and vitro, LPS was injected into mice or administered to THP-1 cells to generate sepsis or inflammatory models. We identified that uridine phosphorylase 1 (UPP1) was upregulated in lung tissues and septic blood samples and uridine significantly alleviated lung injury, inflammation, tissue iron level and lipid peroxidation. Nonetheless, the expression of ferroptosis biomarkers, including SLC7A11, GPX4 and HO-1, were upregulated, while lipid synthesis gene (ACSL4) expression was greatly restricted by uridine supplementation. Moreover, pretreatment of ferroptosis inducer (Erastin or Era) weakened while inhibitor (Ferrostatin-1 or Fer-1) strengthened the protective effects of uridine. Mechanistically, uridine inhibited macrophage ferroptosis by activating Nrf2 signaling pathway. In conclusion, uridine metabolism dysregulation is a novel accelerator for sepsis-induced ALI and uridine supplementation may offer a potential avenue for ameliorating sepsis-induced ALI by suppressing ferroptosis. |
| first_indexed | 2024-03-11T06:26:59Z |
| format | Article |
| id | doaj.art-53583a6ee9dd4e18a6ad172ea04d2582 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T06:26:59Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-53583a6ee9dd4e18a6ad172ea04d25822023-11-17T11:28:57ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01246509310.3390/ijms24065093Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of MacrophageKai Lai0Congkuan Song1Minglang Gao2Yu Deng3Zilong Lu4Ning Li5Qing Geng6Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaDepartment of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaDepartment of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaDepartment of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaDepartment of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaDepartment of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaDepartment of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaUridine metabolism is extensively reported to be involved in combating oxidative stress. Redox-imbalance-mediated ferroptosis plays a pivotal role in sepsis-induced acute lung injury (ALI). This study aims to explore the role of uridine metabolism in sepsis-induced ALI and the regulatory mechanism of uridine in ferroptosis. The Gene Expression Omnibus (GEO) datasets including lung tissues in lipopolysaccharides (LPS) -induced ALI model or human blood sample of sepsis were collected. In vivo and vitro, LPS was injected into mice or administered to THP-1 cells to generate sepsis or inflammatory models. We identified that uridine phosphorylase 1 (UPP1) was upregulated in lung tissues and septic blood samples and uridine significantly alleviated lung injury, inflammation, tissue iron level and lipid peroxidation. Nonetheless, the expression of ferroptosis biomarkers, including SLC7A11, GPX4 and HO-1, were upregulated, while lipid synthesis gene (ACSL4) expression was greatly restricted by uridine supplementation. Moreover, pretreatment of ferroptosis inducer (Erastin or Era) weakened while inhibitor (Ferrostatin-1 or Fer-1) strengthened the protective effects of uridine. Mechanistically, uridine inhibited macrophage ferroptosis by activating Nrf2 signaling pathway. In conclusion, uridine metabolism dysregulation is a novel accelerator for sepsis-induced ALI and uridine supplementation may offer a potential avenue for ameliorating sepsis-induced ALI by suppressing ferroptosis.https://www.mdpi.com/1422-0067/24/6/5093uridineacute lung injuryferroptosismacrophageoxidative stress |
| spellingShingle | Kai Lai Congkuan Song Minglang Gao Yu Deng Zilong Lu Ning Li Qing Geng Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage International Journal of Molecular Sciences uridine acute lung injury ferroptosis macrophage oxidative stress |
| title | Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage |
| title_full | Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage |
| title_fullStr | Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage |
| title_full_unstemmed | Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage |
| title_short | Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage |
| title_sort | uridine alleviates sepsis induced acute lung injury by inhibiting ferroptosis of macrophage |
| topic | uridine acute lung injury ferroptosis macrophage oxidative stress |
| url | https://www.mdpi.com/1422-0067/24/6/5093 |
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