Dexmedetomidine Protects Against Septic Liver Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT1 Signaling Pathway
Background: Liver injury is one of the serious complications of sepsis. Previous studies suggested that dexmedetomidine (DEX) could alleviate cecal ligation and puncture (CLP)-induced liver injury. However, it is unclear whether the protective effect of DEX on sepsis-induced liver injury is related...
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.658677/full |
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| author | Qing Yu Qing Yu Qing Yu Liying Zou Liying Zou Liying Zou Xiu Yuan Xiu Yuan Fang Fang Fang Fang Fang Fang Feng Xu |
| author_facet | Qing Yu Qing Yu Qing Yu Liying Zou Liying Zou Liying Zou Xiu Yuan Xiu Yuan Fang Fang Fang Fang Fang Fang Feng Xu |
| author_sort | Qing Yu |
| collection | DOAJ |
| description | Background: Liver injury is one of the serious complications of sepsis. Previous studies suggested that dexmedetomidine (DEX) could alleviate cecal ligation and puncture (CLP)-induced liver injury. However, it is unclear whether the protective effect of DEX on sepsis-induced liver injury is related to autophagy.Methods: Mice (n = 105) were randomly divided into the following groups: (i) CON group (Sham); (ii) CLP group (CLP-induced liver injury + saline); (iii) CLP + DEX group (CLP-induced liver injury + DEX). Mouse models of sepsis-induced liver injury were established using CLP. DEX or normal saline was administered by intraperitoneal injection at 0, 2, and 4 h after CLP surgery. The mortality rate within 120 h was calculated. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and inflammatory cytokines were measured at 6, 12, and 24 h in each group. Hematoxylin and eosin staining assay was carried out to detect the morphological changes of mouse liver cells in each group. The levels of autophagy-associated proteins LC3II, Beclin-1, p62, and LAMP-2 were detected in three groups of mice using western blotting. The expression of LC3II was detected using immunofluorescence. Transmission electron microscopy (TEM) of liver tissue was used to observe autophagosomes and autophagosome–lysosomes. Lastly, the effect of DEX on the AMPK/SIRT1 pathway-associated protein levels were detected using western blotting. Meanwhile, we used L0-2 cells infected with mRFP-GFP-LC3 adenovirus to further analyze the role of SIRT1 in DEX-induced autophagy in liver injury model in vitro.Results: DEX significantly improved the survival rate of septic mice at the early stage and ameliorated the pathology of sepsis-induced liver injury. The level of autophagy-associated proteins, phosphorylated (p)-AMPK/AMPK, and SIRT1 in the liver of CLP-induced sepsis mice peaked at 12 h post-CLP and decreased significantly at 24 h. In the CLP + DEX group, the levels of autophagy-associated proteins, p-AMPK/AMPK, and SIRT1 increased, whereas inflammatory cytokines decreased at 24 h. The autophagosome structure was clearly observed at different time points in the CLP + DEX group. In the in vitro hepatocyte injury model, the SIRT1 inhibitor significantly increased intracellular ROS levels and reversed the effect of DEX on autophagy flux.Conclusion: We demonstrated a novel mechanism in which DEX protects against CLP-induced liver injury. DEX enhances autophagy, which alleviates the inflammatory responses in CLP-induced liver injury by regulating the SIRT1/AMPK pathway. |
| first_indexed | 2024-12-17T08:30:04Z |
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| last_indexed | 2024-12-17T08:30:04Z |
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| spelling | doaj.art-3d929825bee14d9785a42718681987cb2022-12-21T21:56:37ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-04-011210.3389/fphar.2021.658677658677Dexmedetomidine Protects Against Septic Liver Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT1 Signaling PathwayQing Yu0Qing Yu1Qing Yu2Liying Zou3Liying Zou4Liying Zou5Xiu Yuan6Xiu Yuan7Fang Fang8Fang Fang9Fang Fang10Feng Xu11Department of Intensive Care Unit, Children's Hospital of Chongqing Medical University, Chongqing, ChinaMinistry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, ChinaChongqing Key Laboratory of Pediatrics, Chongqing, ChinaDepartment of Intensive Care Unit, Children's Hospital of Chongqing Medical University, Chongqing, ChinaMinistry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, ChinaChongqing Key Laboratory of Pediatrics, Chongqing, ChinaMinistry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, ChinaChongqing Key Laboratory of Pediatrics, Chongqing, ChinaDepartment of Intensive Care Unit, Children's Hospital of Chongqing Medical University, Chongqing, ChinaMinistry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, ChinaChongqing Key Laboratory of Pediatrics, Chongqing, ChinaDepartment of Intensive Care Unit, Children's Hospital of Chongqing Medical University, Chongqing, ChinaBackground: Liver injury is one of the serious complications of sepsis. Previous studies suggested that dexmedetomidine (DEX) could alleviate cecal ligation and puncture (CLP)-induced liver injury. However, it is unclear whether the protective effect of DEX on sepsis-induced liver injury is related to autophagy.Methods: Mice (n = 105) were randomly divided into the following groups: (i) CON group (Sham); (ii) CLP group (CLP-induced liver injury + saline); (iii) CLP + DEX group (CLP-induced liver injury + DEX). Mouse models of sepsis-induced liver injury were established using CLP. DEX or normal saline was administered by intraperitoneal injection at 0, 2, and 4 h after CLP surgery. The mortality rate within 120 h was calculated. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and inflammatory cytokines were measured at 6, 12, and 24 h in each group. Hematoxylin and eosin staining assay was carried out to detect the morphological changes of mouse liver cells in each group. The levels of autophagy-associated proteins LC3II, Beclin-1, p62, and LAMP-2 were detected in three groups of mice using western blotting. The expression of LC3II was detected using immunofluorescence. Transmission electron microscopy (TEM) of liver tissue was used to observe autophagosomes and autophagosome–lysosomes. Lastly, the effect of DEX on the AMPK/SIRT1 pathway-associated protein levels were detected using western blotting. Meanwhile, we used L0-2 cells infected with mRFP-GFP-LC3 adenovirus to further analyze the role of SIRT1 in DEX-induced autophagy in liver injury model in vitro.Results: DEX significantly improved the survival rate of septic mice at the early stage and ameliorated the pathology of sepsis-induced liver injury. The level of autophagy-associated proteins, phosphorylated (p)-AMPK/AMPK, and SIRT1 in the liver of CLP-induced sepsis mice peaked at 12 h post-CLP and decreased significantly at 24 h. In the CLP + DEX group, the levels of autophagy-associated proteins, p-AMPK/AMPK, and SIRT1 increased, whereas inflammatory cytokines decreased at 24 h. The autophagosome structure was clearly observed at different time points in the CLP + DEX group. In the in vitro hepatocyte injury model, the SIRT1 inhibitor significantly increased intracellular ROS levels and reversed the effect of DEX on autophagy flux.Conclusion: We demonstrated a novel mechanism in which DEX protects against CLP-induced liver injury. DEX enhances autophagy, which alleviates the inflammatory responses in CLP-induced liver injury by regulating the SIRT1/AMPK pathway.https://www.frontiersin.org/articles/10.3389/fphar.2021.658677/fullsepsisliver injurydexmedetomidineautophagyclp |
| spellingShingle | Qing Yu Qing Yu Qing Yu Liying Zou Liying Zou Liying Zou Xiu Yuan Xiu Yuan Fang Fang Fang Fang Fang Fang Feng Xu Dexmedetomidine Protects Against Septic Liver Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT1 Signaling Pathway Frontiers in Pharmacology sepsis liver injury dexmedetomidine autophagy clp |
| title | Dexmedetomidine Protects Against Septic Liver Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT1 Signaling Pathway |
| title_full | Dexmedetomidine Protects Against Septic Liver Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT1 Signaling Pathway |
| title_fullStr | Dexmedetomidine Protects Against Septic Liver Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT1 Signaling Pathway |
| title_full_unstemmed | Dexmedetomidine Protects Against Septic Liver Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT1 Signaling Pathway |
| title_short | Dexmedetomidine Protects Against Septic Liver Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT1 Signaling Pathway |
| title_sort | dexmedetomidine protects against septic liver injury by enhancing autophagy through activation of the ampk sirt1 signaling pathway |
| topic | sepsis liver injury dexmedetomidine autophagy clp |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.658677/full |
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