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
| Autor: | Kai Song, Cui Li, Xiangyun Li, Xinxin Hu, Zilei Xie, Haibo Li, Jia Shi, Shihan Du, Yuan Zhang, Si-meng He, Jianbo Yu, Shuan Dong, Tianxi Yu |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Mitochondrial ROS Lipopolysaccharides Medicine (General) Clinical Biochemistry Mitochondrion medicine.disease_cause Biochemistry Mfn1 mitofusin 1 Mitochondrial Dynamics Rats Sprague-Dawley Mice 0302 clinical medicine Endotoxin Biology (General) DEX dexmedetomidine HO-1 heme oxygenase-1 Chemistry HIF-1α hypoxia inducible factor-1α NR8383 rat alveolar macrophage cell line NR8383 Cell biology OPA1 optic atrophy 1 mitochondrial fusion Heme oxygenase-1 LPS lipopolysaccharide Signal transduction Dexmedetomidine Research Paper Signal Transduction QH301-705.5 Acute Lung Injury Lung injury Mfn2 mitofusin 2 03 medical and health sciences R5-920 ROS reactive oxygen species Downregulation and upregulation In vivo medicine Hypoxia-inducible factor 1 siRNA small interfering RNA (siRNA) Animals NC siRNA negative control siRNA Fis1 fission 1 Drp1 dynamin-related protein 1 KO knockout DMOG dimethyloxalylglycine OSI oxidative stress indices Organic Chemistry Rats Endotoxins Mice Inbred C57BL Oxidative Stress 030104 developmental biology 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Redox Biology Redox Biology, Vol 41, Iss, Pp 101954-(2021) |
| ISSN: | 2213-2317 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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