Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway
Increasing lines of evidence identified that dexmedetomidine (DEX) exerted protective effects against sepsis-stimulated acute lung injury via anti-inflammation, anti-oxidation and anti-apoptosis. However, the mechanisms remain unclear. Herein, we investigated whether DEX afforded lung protection by...
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Elsevier
2021-05-01
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Series: | Redox Biology |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231721001026 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jia Shi Tianxi Yu Kai Song Shihan Du Simeng He Xinxin Hu Xiangyun Li Haibo Li Shuan Dong Yuan Zhang Zilei Xie Cui Li Jianbo Yu |
spellingShingle |
Jia Shi Tianxi Yu Kai Song Shihan Du Simeng He Xinxin Hu Xiangyun Li Haibo Li Shuan Dong Yuan Zhang Zilei Xie Cui Li Jianbo Yu Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway Redox Biology Dexmedetomidine Endotoxin Acute lung injury Mitochondrial dynamics Hypoxia-inducible factor 1 Heme oxygenase-1 |
author_facet |
Jia Shi Tianxi Yu Kai Song Shihan Du Simeng He Xinxin Hu Xiangyun Li Haibo Li Shuan Dong Yuan Zhang Zilei Xie Cui Li Jianbo Yu |
author_sort |
Jia Shi |
title |
Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway |
title_short |
Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway |
title_full |
Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway |
title_fullStr |
Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway |
title_full_unstemmed |
Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway |
title_sort |
dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the hif-1a/ho-1 signaling pathway |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2021-05-01 |
description |
Increasing lines of evidence identified that dexmedetomidine (DEX) exerted protective effects against sepsis-stimulated acute lung injury via anti-inflammation, anti-oxidation and anti-apoptosis. However, the mechanisms remain unclear. Herein, we investigated whether DEX afforded lung protection by regulating the process of mitochondrial dynamics through the HIF-1a/HO-1 pathway in vivo and in vitro. Using C57BL/6J mice exposed to lipopolysaccharide, it was initially observed that preemptive administration of DEX (50μg/kg) alleviated lung pathologic injury, reduced oxidative stress indices (OSI), improved mitochondrial dysfunction, upregulated the expression of HIF-1α and HO-1, accompanied by shifting the dynamic course of mitochondria into fusion. Moreover, HO-1-knockout mice or HO-1 siRNA transfected NR8383 cells were pretreated with HIF-1α stabilizer DMOG and DEX to validate the effect of HIF-1a/HO-1 pathway on DEX-mediated mitochondrial dynamics in a model of endotoxin-induced lung injury. We found that pretreatment with DEX and DMOG distinctly relieved lung injury, decreased the levels of mitochondrial ROS and mtDNA, reduced OSI, increased nuclear accumulation of HIF-1a and HO-1 protein in wild type mice but not HO-1 KO mice. Similar observations were recapitulated in NC siRNA transfected NR8383 cells after LPS stimulation but not HO-1 siRNA transfected cells. Concertedly, DEX reversed the impaired mitochondrial morphology in LPS stimulated-wild type mice or NC siRNA transfected NR8383 cells, upregulated the expression of mitochondrial fusion protein, while downregulated the expression of fission protein in HIF-1a/HO-1 dependent pathway. Altogether, our data both in vivo and in vitro certified that DEX treatment ameliorated endotoxin-induced acute lung injury by preserving the dynamic equilibrium of mitochondrial fusion/fission through the regulation of HIF-1a/HO-1 signaling pathway. |
topic |
Dexmedetomidine Endotoxin Acute lung injury Mitochondrial dynamics Hypoxia-inducible factor 1 Heme oxygenase-1 |
url |
http://www.sciencedirect.com/science/article/pii/S2213231721001026 |
work_keys_str_mv |
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1721494751551684608 |
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doaj-ee72139b4da34433a0d67a27e3bc17d82021-05-02T05:54:35ZengElsevierRedox Biology2213-23172021-05-0141101954Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathwayJia Shi0Tianxi Yu1Kai Song2Shihan Du3Simeng He4Xinxin Hu5Xiangyun Li6Haibo Li7Shuan Dong8Yuan Zhang9Zilei Xie10Cui Li11Jianbo Yu12Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, ChinaDepartment of Sanitary Inspection and Quarantine, Kunming Medical University, YunNan, ChinaDepartment of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, ChinaDepartment of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, ChinaDepartment of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Nankai University, Tianjin, ChinaDepartment of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, ChinaDepartment of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, ChinaDepartment of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, ChinaDepartment of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, ChinaDepartment of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, ChinaDepartment of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, ChinaDepartment of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, ChinaDepartment of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China; Corresponding author. Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, 6 Changjiang Road, Tianjin, 300100, China.Increasing lines of evidence identified that dexmedetomidine (DEX) exerted protective effects against sepsis-stimulated acute lung injury via anti-inflammation, anti-oxidation and anti-apoptosis. However, the mechanisms remain unclear. Herein, we investigated whether DEX afforded lung protection by regulating the process of mitochondrial dynamics through the HIF-1a/HO-1 pathway in vivo and in vitro. Using C57BL/6J mice exposed to lipopolysaccharide, it was initially observed that preemptive administration of DEX (50μg/kg) alleviated lung pathologic injury, reduced oxidative stress indices (OSI), improved mitochondrial dysfunction, upregulated the expression of HIF-1α and HO-1, accompanied by shifting the dynamic course of mitochondria into fusion. Moreover, HO-1-knockout mice or HO-1 siRNA transfected NR8383 cells were pretreated with HIF-1α stabilizer DMOG and DEX to validate the effect of HIF-1a/HO-1 pathway on DEX-mediated mitochondrial dynamics in a model of endotoxin-induced lung injury. We found that pretreatment with DEX and DMOG distinctly relieved lung injury, decreased the levels of mitochondrial ROS and mtDNA, reduced OSI, increased nuclear accumulation of HIF-1a and HO-1 protein in wild type mice but not HO-1 KO mice. Similar observations were recapitulated in NC siRNA transfected NR8383 cells after LPS stimulation but not HO-1 siRNA transfected cells. Concertedly, DEX reversed the impaired mitochondrial morphology in LPS stimulated-wild type mice or NC siRNA transfected NR8383 cells, upregulated the expression of mitochondrial fusion protein, while downregulated the expression of fission protein in HIF-1a/HO-1 dependent pathway. Altogether, our data both in vivo and in vitro certified that DEX treatment ameliorated endotoxin-induced acute lung injury by preserving the dynamic equilibrium of mitochondrial fusion/fission through the regulation of HIF-1a/HO-1 signaling pathway.http://www.sciencedirect.com/science/article/pii/S2213231721001026DexmedetomidineEndotoxinAcute lung injuryMitochondrial dynamicsHypoxia-inducible factor 1Heme oxygenase-1 |