Dexmedetomidine reduces ventilator-induced lung injury (VILI) by inhibiting Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway

Chen, Hongli; Sun, Xiaotong; Yang, Xiaomei; Hou, Yonghao; Yu, Xiaoqian; Wang, Yang; Wu, Jianbo; Liu, Dejie; Wang, Huanliang; J, Yu; Yi, Wenbo

doi:10.17305/bjbms.2018.2400

Cited by 25 publications

(15 citation statements)

References 30 publications

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“…Meanwhile, LPS significantly increased the production of TNF-α, IL-6, IL-1β, IL-2, IL-12 and MCP-1 in BV2 cells. Chen et al found that Dex reduces lung injury via inhibiting NF-κB signaling pathway, which was consistent with our results 41. These data indicated that Dex could decrease neuroinflammation in LPS-stimulated BV2 cells via inhibiting NF-κB.…”

Section: Discussionsupporting

confidence: 93%

<p>Dexmedetomidine Attenuates Neuroinflammation In LPS-Stimulated BV2 Microglia Cells Through Upregulation Of miR-340</p>

Yang

Zhu

et al. 2019

DDDT

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BackgroundDexmedetomidine (Dex) was reported to exhibit anti-inflammatory effect in the nervous system. However, the mechanism by which Dex exhibits anti-inflammation effects on LPS-stimulated BV2 microglia cells remains unclear. Thus, this study aimed to investigate the role of Dex in LPS-stimulated BV2 cells.MethodsThe BV2 cells were stimulated by lipopolysaccharides (LPS). BV2 cells were infected with short-hairpin RNAs targeting NF-κB (NF-κB-shRNAs) and NF-κB overexpression lentivirus, respectively. In addition, miR-340 mimics or miR-340 inhibitor was transfected into BV2 cells, respectively. Meanwhile, the dual-luciferase reporter system assay was used to explore the interaction of miR-340 and NF-κB in BV2 cells. CCK-8 was used to detect the viability of BV2 cells. In addition, Western blotting was used to detect the level of NF-κB in LPS-stimulated BV2 cells. The levels of TNF-α, IL-6, IL-1β, IL-2, IL-12, IL-10 and MCP-1 in LPS-stimulated BV2 cells were measured with ELISA.ResultsThe level of miR-340 was significantly upregulated in Dex-treated BV2 cells. Meanwhile, the level of NF-κB was significantly increased in BV2 cells following infection with lenti-NF-κB, which was markedly reversed by Dex. LPS markedly increased the expression of NF-κB and proinflammatory cytokines in BV2 cells, which were reversed in the presence of Dex. Moreover, miR-340 mimics enhanced the anti-inflammatory effects of Dex in LPS-stimulated BV2 cells via inhibiting NF-κB and proinflammatory cytokines. Furthermore, Dex obviously inhibited LPS-induced phagocytosis in BV2 cells.ConclusionTaken together, our results suggested that Dex might exert anti-inflammatory effects in LPS-stimulated BV2 cells via upregulation of miR-340. Therefore, Dex might serve as a potential agent for the treatment of neuroinflammation.

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Section: Discussionsupporting

confidence: 93%

<p>Dexmedetomidine Attenuates Neuroinflammation In LPS-Stimulated BV2 Microglia Cells Through Upregulation Of miR-340</p>

Yang

Zhu

et al. 2019

DDDT

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“…MV is a life-saving therapy for ardS and patients with acute respiratory failure, such as acute lung injury, and is critical in general anesthesia (12). However, excessive ventilation can exacerbate pre-existing lung damage and damage healthy lungs, this process is known as Vili (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have also reported the anti-inflammatory effects of Dex by reducing the expression of inflammatory factors in certain specific cases (27)(28)(29). Considering previous literature reports and clinical dose analysis (11,12), two doses of dex were examined in the present study. The data showed that high doses of Dex at 10 µg/kg/h significantly decreased expression of the inflammation-related cytokines IL-1β, il-6 and TnF-α, W/d ratios and pathological changes in the Vili model rats.…”

Section: Discussionmentioning

confidence: 99%

“…ample evidence has been reported on the protective effects of MV on organs (9). it has been demonstrated that dex could ameliorate Vili-induced pulmonary inflammation in animal models (10,11); Chen et al (12) observed that dex reduces VILI induced inflammation by inhibiting Tlr4 and nF-κB signaling through α2-adrenoreceptors. However, the exact mechanism has yet to be established.…”

Section: Introductionmentioning

confidence: 99%

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Dexmedetomidine reduces ventilator-induced lung injury via ERK1/2 pathway activation

Zhu

Ben-qing

et al. 2020

Mol Med Rep

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Mechanical ventilation (MV) can contribute to ventilator-induced lung injury (Vili); dexmedetomidine (dex) treatment attenuates MV-related pulmonary inflammation, but the mechanisms remain unclear. Therefore, the present study aimed to explore the protective effect and the possible molecular mechanisms of dex in a Vili rodent model. adult male Sprague-dawley rats were randomly assigned to one of seven groups (n=24 rats/group). rats were euthanized after 4 h of continuous MV, and pathological changes, lung wet/dry (W/D) weight ratio, the levels of inflammatory cytokines (il-1β, TnF-α and il-6) in the bronchoalveolar lavage fluid (BALF), and the expression levels of Bcl-2 homologous antagonist/killer (Bak), Bcl-2, pro-caspase-3, cleaved caspase-3 and the phosphorylation of erK1/2 in the lung tissues were measured. Propidium iodide uptake and Tunel staining were used to detect epithelial cell death. The dex pretreatment group exhibited fewer pathological changes, lower W/d ratios and lower expression levels of inflammatory cytokines in BALF compared with the VILI group. Dex significantly attenuated the ratio of Bak/Bcl-2, cleaved caspase-3 expression levels and epithelial cell death, and increased the expression of phosphorylated erK1/2. The protective effects of dex could be partially reversed by Pd98059, which is a mitogen-activated protein kinase (upstream of erK1/2) inhibitor. overall, dexmedetomidine was found to reduce the inflammatory response and epithelial cell death caused by Vili, via the activation of the erK1/2 signaling pathway.

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“…Many studies have veri ed that DEX attenuates ischemiareperfusion injury and lipopolysaccharide and ventilator-induced lung injury. [10][11][12][13] However, the speci c mechanism remains unknown. According to a recent report, α 2 -adrenergic stimulation suppresses oxidative damage and alters the mitochondrial membrane potential (MMP), 14 suggesting that dexmedetomidine, a speci c α 2 -adrenoreceptor agonist, probably exerted a protective effect by in uencing mitochondrial function.…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine Attenuates Lung Ischemia-reperfusion Injury in Rats by Reducing Mitochondrial Dysfunction

Zhang¹,

Lu²,

Wang³

et al. 2020

Preprint

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Background: Lung ischemia-reperfusion injury (LIRI) is a significant clinical problem occurring after lung transplantation. LIRI is mediated by the overproduction of reactive oxygen species (ROS) and inflammatory activation. Previous studies have confirmed that dexmedetomidine (DEX) exerts a protective effect on LIRI, which potentially causes severe mitochondrial dysfunction. However, the specific mechanisms remain unclear. Our study was to explore whether dexmedetomidine exerts a beneficial effect on LIRI by reducing mitochondrial dysfunction. Methods: Two different models were used in our study. For the in vivo experiment, thirty-two male Sprague-Dawley rats were randomly divided into Sham, ischemia-reperfusion (I/R), DEX+I/R and DEX+yohimbine+I/R (DY+I/R) groups. Similarly, pulmonary vascular endothelial cells (PVECs) from SD rats were divided into Control, oxygen glucose deprivation (OGD), D+OGD and DY+OGD groups.Results: In our experiment, we confirmed severe lung damage after LIRI that was characterized by significantly pulmonary histopathology injury, a decrease in the oxygenation index (PaO2/FiO2) and an increase in the wet-to-dry weight ratio, while DEX treatment mitigated this damage. In addition, the DEX pretreatment significantly attenuated I/R-induced oxidative stress by decreasing the level of ROS in the mitochondria in vitro. Moreover, the DEX treatment enhanced mitochondrial biogenesis and autophagy by increasing the expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), mitochondrial transcription factor A (Tfam), PTEN-induced putative kinase 1 (PINK1), Parkin and dynamin 1-like protein 1 (Drp1). Conclusions: These data suggest that DEX may alleviate LIRI by reducing mitochondrial dysfunction through the induction of mitochondrial biogenesis and autophagy.

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Dexmedetomidine reduces ventilator-induced lung injury (VILI) by inhibiting Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway

Cited by 25 publications

References 30 publications

<p>Dexmedetomidine Attenuates Neuroinflammation In LPS-Stimulated BV2 Microglia Cells Through Upregulation Of miR-340</p>

<p>Dexmedetomidine Attenuates Neuroinflammation In LPS-Stimulated BV2 Microglia Cells Through Upregulation Of miR-340</p>

Dexmedetomidine reduces ventilator-induced lung injury via ERK1/2 pathway activation

Dexmedetomidine Attenuates Lung Ischemia-reperfusion Injury in Rats by Reducing Mitochondrial Dysfunction

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