The protective effect of dexmedetomidine on LPS-induced acute lung injury through the HMGB1-mediated TLR4/NF-κB and PI3K/Akt/mTOR pathways

Meng, Ling; Li, Longyun; Lu, Shan; Li, Kai; Su, Zhenbo; Wang, Yunyun; Fan, Xiaodi; Li, Xuyang; Zhao, Guoqing

doi:10.1016/j.molimm.2017.12.008

Cited by 267 publications

(194 citation statements)

References 25 publications

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“…Also, the protective effects of DEX were reported to be associated with other pathways. For example, DEX could exert its protective effects on lipopolysaccharide‐induced acute lung injury rats via the PI3K/Akt/mTOR pathways and on myeloma via the NEAT1/miR‐193a/MCL1 pathway …”

Section: Discussionmentioning

confidence: 99%

“…For example, DEX could exert its protective effects on lipopolysaccharide-induced acute lung injury rats via the PI3K/Akt/mTOR pathways and on myeloma via the NEAT1/miR-193a/MCL1 pathway. 27,28 In subsequent experiments, the researchers demonstrated that MEG3 influenced HIBD by binding to miR-129-5p in neonatal mice. In recent years, an interaction between lncRNAs and miRNAs has been observed, which signified that the lncRNAs are able to bind to miRNAs by competing with other miRNAs.…”

Section: Discussionmentioning

confidence: 99%

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Silencing of long noncoding RNA MEG3 enhances cerebral protection of dexmedetomidine against hypoxic‐ischemic brain damage in neonatal mice by binding to miR‐129‐5p

Zhou

Liu

Wang

et al. 2018

J of Cellular Biochemistry

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Hypoxic‐ischemic brain damage (HIBD) is a leading cause of neonatal acute mortality and chronic nervous system injury. Recently, it has been found that long noncoding RNAs (lncRNAs) play a significant role in the neurodevelopment and etiopathogenesis of HIBD. Here, the researchers aimed to determine the role of lncRNA maternally expressed gene (MEG3) in the therapeutic effect of dexmedetomidine (DEX) in neonatal mice with HIBD through the regulation of microRNA‐129‐5p (miR‐129‐5p). HIBD models were established in C57/BL6 neonatal mice. Subsequently, the target relationship between MEG3 and miR‐129‐5p was predicted and verified. The neonatal mice were injected with DEX, ad‐shMEG3, and mimics and inhibitors of miR‐129‐5p to identify roles of MEG3 and miR‐129‐5p in therapeutic effects of DEX on neuronal apoptosis and injury, cerebral atrophy, and learning and memory ability of neonatal mice with HIBD. MEG3 directly targeted and inhibited the expression of miR‐129‐5p. Silencing of MEG3 or upregulation of miR‐129‐5p effectively promoted the therapeutic effect of DEX on neonatal mice with HIBD. Silencing of MEG3 or upregulation of miR‐129‐5p reduced the neuronal apoptosis rate and degree of cerebral atrophy, and also enhanced the learning and memory ability of HIBD neonatal mice. Collectively, the key findings obtained from the present study support the notion that MEG3 silencing enhances the therapeutic effect of DEX on neonatal mice with HIBD by binding to miR‐129‐5p.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Silencing of long noncoding RNA MEG3 enhances cerebral protection of dexmedetomidine against hypoxic‐ischemic brain damage in neonatal mice by binding to miR‐129‐5p

Zhou

Liu

Wang

et al. 2018

J of Cellular Biochemistry

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“…Adminstration of dexmedetomidine has been demonstrated to increase the discharge frequency of cervical vagus nerves resulting in reduced release of proinflammatory mediators and improved survival in experimental endotoxemia (Xiang et al 2014). Histological studies of lung sections from LPSinduced lung injury revealed reduced expression of TLR4 and HMGB1 (Meng et al 2018).…”

Section: Dexmedetomidinementioning

confidence: 99%

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Andersson

Ottestad

Tracey

2020

Mol Med

202

212

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Background: The 2019 novel coronavirus disease (COVID-19) causes for unresolved reasons acute respiratory distress syndrome in vulnerable individuals. There is a need to identify key pathogenic molecules in COVID-19-associated inflammation attainable to target with existing therapeutic compounds. The endogenous damage-associated molecular pattern (DAMP) molecule HMGB1 initiates inflammation via two separate pathways. Disulfide-HMGB1 triggers TLR4 receptors generating pro-inflammatory cytokine release. Extracellular HMGB1, released from dying cells or secreted by activated innate immunity cells, forms complexes with extracellular DNA, RNA and other DAMP or pathogen-associated molecular (DAMP) molecules released after lytic cell death. These complexes are endocytosed via RAGE, constitutively expressed at high levels in the lungs only, and transported to the endolysosomal system, which is disrupted by HMGB1 at high concentrations. Danger molecules thus get access to cytosolic proinflammatory receptors instigating inflammasome activation. It is conceivable that extracellular SARS-CoV-2 RNA may reach the cellular cytosol via HMGB1-assisted transfer combined with lysosome leakage. Extracellular HMGB1 generally exists in vivo bound to other molecules, including PAMPs and DAMPs. It is plausible that these complexes are specifically removed in the lungs revealed by a 40% reduction of HMGB1 plasma levels in arterial versus venous blood. Abundant pulmonary RAGE expression enables endocytosis of danger molecules to be destroyed in the lysosomes at physiological HMGB1 levels, but causing detrimental inflammasome activation at high levels. Stress induces apoptosis in pulmonary endothelial cells from females but necrosis in cells from males.Conclusion: Based on these observations we propose extracellular HMGB1 to be considered as a therapeutic target for COVID-19.

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“…Dex has been shown to attenuate the isoflurane-induced neuronal injury in the hippocampus of neonatal rats in a dose-dependent manner and prevent the isoflurane-induced long-term memory impairment 20,21. Dex also exerts a protective effect on lipopolysaccharide-induced acute lung injury by mediating the PI3K/Akt/mTOR pathway 22. However, it is unclear whether treatment with Dex can mitigate the propofol-induced long-term neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine attenuates the propofol-induced long-term neurotoxicity in the developing brain of rats by enhancing the PI3K/Akt signaling pathway

Xiao

Zhou

et al. 2018

NDT

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BackgroundPropofol induces short- and long-term neurotoxicity. Our previous study showed that dexmedetomidine (Dex) can attenuate the propofol-induced acute neurotoxicity in rodents by enhancing the PI3K/Akt signaling. However, whether treatment of young rats with Dex could protect them from long-term neurotoxicity induced by propofol is unclear.Materials and methodsSeven-day-old male Sprague Dawley rats were randomized and injected intraperitoneally with saline (100 μL, NS), propofol (100 mg/kg), Dex (75 μg/kg), propofol (100 mg/kg) plus Dex (25, 50 or 75 μg/kg), 10% dimethyl sulfoxide (DMSO, 100 μL) or TDZD-8 (a GSK3β inhibitor, 1 mg/kg), or intracerebroventricularly with DMSO (5 μL) or LY294002 (a PI3K inhibitor, 25 μg/5 μL DMSO). Other rats in the experimental group were injected with the same doses of propofol, Dex and LY294002 or TDZD-8. All the rats were monitored until they were 9 weeks old. Their spatial learning and memory were tested by Morris water maze. The neuronal apoptosis, expression of PSD95, expression and phosphorylation of Akt and GSK3β and synaptic ultrastructures were determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, immunohistochemistry, Western blot and transmission electron microscopy assays, respectively.ResultsCompared with the NS control group, young rats injected with intralipid, Dex, TDZD-8, LY294002 or DMSO alone did not show any significant change as they aged. Propofol significantly increased the escape latency time, hippocampal neuroapoptosis and synaptic ultrastructural changes but decreased the relative levels of PSD95 expression, and Akt and GSK3β phosphorylation in the developing hippocampus of the rats. The neuronal toxic effects of propofol were significantly mitigated by the pretreatment with a higher dose of Dex. The neuroprotective effect of Dex was enhanced by the treatment with TDZD-8, but was completely abrogated by the treatment with LY294002.ConclusionOur results indicated that the pretreatment of young rats with Dex attenuated the propofol-induced long-term neurotoxicity in their developing hippocampus by enhancing the PI3K/Akt signaling.

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The protective effect of dexmedetomidine on LPS-induced acute lung injury through the HMGB1-mediated TLR4/NF-κB and PI3K/Akt/mTOR pathways

Cited by 267 publications

References 25 publications

Silencing of long noncoding RNA MEG3 enhances cerebral protection of dexmedetomidine against hypoxic‐ischemic brain damage in neonatal mice by binding to miR‐129‐5p

Silencing of long noncoding RNA MEG3 enhances cerebral protection of dexmedetomidine against hypoxic‐ischemic brain damage in neonatal mice by binding to miR‐129‐5p

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

Dexmedetomidine attenuates the propofol-induced long-term neurotoxicity in the developing brain of rats by enhancing the PI3K/Akt signaling pathway

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