Dexmedetomidine Attenuates Myocardial Injury Induced by Renal Ischemia/Reperfusion by Inhibiting the HMGB1-TLR4-MyD88-NF-κB Signaling Pathway.

To investigate the effect of dexmedetomidine (DEX) on myocardial injury induced by renal ischemia/reperfusion (I/R) and to explore the role of the HMGB1-TLR4-MyD88-NF-κB signaling pathway. Adult male Wistar rats were randomly allocated into the control group, renal I/R group, renal I/R group pretreated with a low dose of DEX (L-Dex+I/R), renal I/R group pretreated with a medium dose of DEX (M-Dex+I/R), and renal I/R group pretreated with a high dose of DEX (H-Dex+I/R). Outcome measures included the plasma concentrations of HMGB1, IL-6, IL-10, IL-17, and TnI, the expression levels of HMGB1, TLR4, MyD88, NF-κBp65, and P-NF-κBp65, the pathological change, and the cell apoptosis. Renal I/R led to severe myocardial histological injury and cell apoptosis. DEX reduced the plasma concentration of IL-17 and TnI in a dose-dependent manner in the renal I/R model rats and inhibited the protein expression of TLR4 and NF-κBp65 in a dose-dependent manner in the myocardial tissue. Additionally, mRNA expression of MyD88 was elevated in the I/R group compared with the control group, and DEX significantly reduced mRNA expression of MyD88 in the renal I/R model rats. DEX inhibited myocardial cell apoptosis in the renal I/R model rats. DEX could attenuate myocardial injury induced by renal I/R in a dose-dependent manner. The potential mechanisms are associated with inhibition of the HMGB1-TLR4-NF-κB signaling pathway and myocardial cell apoptosis.

Zhang B ，Zhang J ，Ainiwaer Y ，He B ，Geng Q ，Lin L ，Li X ... -  《-》

Dexmedetomidine preconditioning may attenuate myocardial ischemia/reperfusion injury by down-regulating the HMGB1-TLR4-MyD88-NF-кB signaling pathway.

Zhang JJ ，Peng K ，Zhang J ，Meng XW ，Ji FH ... -  《PLoS One》

Dexmedetomidine Post-Conditioning Alleviates Cerebral Ischemia-Reperfusion Injury in Rats by Inhibiting High Mobility Group Protein B1 Group (HMGB1)/Toll-Like Receptor 4 (TLR4)/Nuclear Factor kappa B (NF-κB) Signaling Pathway.

Zhai Y ，Zhu Y ，Liu J ，Xie K ，Yu J ，Yu L ，Deng H ... -  《MEDICAL SCIENCE MONITOR》

Dexmedetomidine Resists Intestinal Ischemia-Reperfusion Injury by Inhibiting TLR4/MyD88/NF-κB Signaling.

Intestinal ischemia/reperfusion (I/R) is a common clinical problem that occurs during various clinical pathological processes. Dexmedetomidine (DEX), a widely used anesthetic adjuvant agent, can induce protection against intestinal I/R in vivo; however, the underlying mechanism is not fully understood. In the present study, we aimed to investigate the protective effects of DEX and examine whether its mechanism was associated with the TLR4/MyD88/NF-κB signaling pathway. Sprague-Dawley rats were pretreated with DEX and then subjected to I/R-induced intestinal injury. In vivo, intestinal histopathological examination and scoring were performed, the levels of serum intestinal fatty acid-binding protein (I-FABP), intestinal tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and expression levels of TLR4, MyD88, and NF-κB in the intestine were determined. In in vitro experiments, the human colon carcinoma cell line (Caco-2) was incubated with DEX before deprivation/reoxygenation (OGD/R) treatment. The cell viability of Caco-2 cells, the levels of lactate dehydrogenase (LDH), TNF-α, and IL-1β in the supernatant, as well as protein expression of TLR4, MyD88, and NF-κB in Caco-2 cells, were measured. Statistical analysis was performed using SPSS version 21.0. DEX preconditioning significantly reduced the intestinal pathological Chiu's score, serum I-FABP, intestinal TNF-α, IL-1β levels, and the protein expression of TLR4, MyD88, and NF-κB in the rats with intestinal I/R injury. Similarly, in vitro, DEX pretreatment protected against OGD/R-induced Caco-2 cell damage and inhibited TLR4/MyD88/NF-κB signaling, as evidenced by increased cell viability, decreased LDH activity, reduced TNF-α and IL-1β levels, as well as downregulated TLR4, MyD88, and NF-κB protein levels. Our findings suggested that DEX could reduce intestinal I/R injury in rats and OGD/R damage in Caco-2 cells, and this protection might be attributed to antiinflammatory effects and inhibition of the TLR4/MyD88/NF-κB signaling pathway.

Yang J ，Wu Y ，Xu Y ，Jia J ，Xi W ，Deng H ，Tu W ... -  《-》

Dexmedetomidine protects against lung injury induced by limb ischemia-reperfusion via the TLR4/MyD88/NF-κB pathway.

Dexmedetomidine (DEX) can protect the lung from ischemia-reperfusion (I/R) injury, but the underlying mechanisms are not fully understood. The aims of this study were to determine whether DEX attenuates lung injury following lower extremity I/R and to investigate the related toll-like receptor 4 (TLR4) signaling pathway. Twenty-eight SD rats were divided into four groups (n = 7): Sham, I/R, I/R + DEX (25 μg/kg prior to ischemia), and I/R + DEX + Atip (250 μg/kg atipamezole before DEX treatment). Lower extremity I/R was induced by left femoral artery clamping for 3 hours and followed by 2 hours reperfusion. Quantitative alveolar damage and the wet/dry (W/D) ratio were calculated. Interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α in the bronchoalveolar lavage fluid (BALF) and serum and myeloperoxidase (MPO) in the lung were measured. The TLR4 and MyD88 mRNA expression levels were measured by RT-PCR, nuclear factor (NF)-κB, and phosphorylated NF-κB by western blot, respectively. Quantitative alveolar damage, W/D ratio, MPO, BALF and serum IL-1, IL-6, and TNF-α, and TLR4, MyD88, NF-κB, and p-NF-κB expression significantly increased in the I/R group relative to the Sham group. DEX preconditioning significantly reduced lung edema, and histological injury relative to the I/R group. Serum and BALF IL-1, IL-6, and TNF-α levels, MPO activity and TLR4, MyD88, NF-κB, and p-NF-κB expression were also significantly reduced in the I/R + DEX group compared with the I/R group. Atipamezole partially reversed all the aforementioned effects. DEX preconditioning protects the lungs against lower extremity I/R injury via α2-adrenoceptor-dependent and α2-adrenoceptor-independent mechanisms. It also suppresses the TLR4 pathway and reduces inflammation.

Xue BB ，Chen BH ，Tang YN ，Weng CW ，Lin LN ... -  《-》