Taurine enhances the protective effect of Dexmedetomidine on sepsis-induced acute lung injury via balancing the immunological system.

Sepsis, an overwhelming systemic inflammatory disease, is the leading cause of acute lung injury (ALI). Despite plenty of researches have been done, effective drugs treating septic ALI are still eagerly needed in the clinic. Dexmedetomidine (Dex), a potent alpha-2 adrenoreceptor agonist, has been reported to possess antioxidant, anti-apoptosis and anti-inflammatory abilities. Taurine, a kind of intracellular free amino acid, has been used to treat various diseases. This study aimed to explore the combination effect of Dex and Taurine on septic ALI and the underlying mechanism in vivo. The establishment of septic ALI was set up in SD rats by cecal ligation and puncture (CLP) operation. Results indicated that Dex or Taurine could reduce septic ALI-induced cell apoptosis via decreasing caspase-3 activity. However, the combination of Dex or Taurine produced greater effect. Besides that, Dex combined with Taurine could better promote cell proliferation with remarkably elevated Ki67 expression. The combination of Dex and Taurine significantly suppressed the activation of NF-κB pathway via inhibiting P65 phosphorylation and P65 nuclear translocation, leading to the down-regulation of interleukin (IL)-6 and IL-1β. Moreover, co-administration of Dex and Taurine alleviated the imbalance of Th1/Th2 induced by septic ALI to a great extent. All in all, our study suggested the synergistic therapeutic effect of Dex and Taurine on septic ALI.

Zhao W ，Jia L ，Yang HJ ，Xue X ，Xu WX ，Cai JQ ，Guo RJ ，Cao CC ... -  《-》

Protective effect of taurine on sepsis‑induced lung injury via inhibiting the p38/MAPK signaling pathway.

Chen J ，Xue X ，Cai J ，Jia L ，Sun B ，Zhao W ... -  《-》

Protective effect of dexmedetomidine in cecal ligation perforation-induced acute lung injury through HMGB1/RAGE pathway regulation and pyroptosis activation.

Sun H ，Hu H ，Xu X ，Fang M ，Tao T ，Liang Z ... -  《-》

Dexmedetomidine ameliorates LPS induced acute lung injury via GSK-3β/STAT3-NF-κB signaling pathway in rats.

Acute lung injury (ALI) is a serious complication of sepsis and an important cause of death in intensive care. Studies have shown that DEX can inhibit inflammation. However, the anti-inflammatory effect and protective mechanism of DEX in lipopolysaccharide (LPS) induced ALI are still unclear. ALI model was established by intraperitoneal injection of LPS (10 mg/kg) in Sprague-Dawley (SD) male rats. Firstly, at 4, 6, 8, 12 and 24 h after LPS treatment, lung injury including pathologic histology, lung edema, and inflammation were detected. The optimal time point for lung injury was determined to be 12 h, at which time DEX was added to further test. Furthermore, STAT3 inhibitor (NSC74859) and GSK-3β inhibitor (SB216763) were added to verify the role of STAT3, GSK-3β and NF-κB in ameliorated ALI. Our results show that DEX pretreatment significantly decreased lung Wet-to-Dry weight (W/D) ratio and MPO activity and ameliorated LPS induced lung histopathological alterations. In addition, we confirmed that DEX can increased the phosphorylation of STAT3 and GSK-3β, and inhibit the phosphorylation of nuclear factor-κB (NF-κB) p65 in the inflammatory response induced by LPS. What's more, NSC74859 inhibited the phosphorylation of STAT3 and reversed the protect effect of DEX on LPS. SB216763 inhibited the phosphorylation of NF-κB and reversed the damage effect of LPS and plays the same anti-inflammatory effect as DEX. In summary, our data demonstrated that DEX can ameliorate ALI induced by LPS through GSK-3β/STAT3-NF-κB pathway.

Zhang H ，Sha J ，Feng X ，Hu X ，Chen Y ，Li B ，Fan H ... -  《-》

Dexmedetomidine-mediated protection against septic liver injury depends on TLR4/MyD88/NF-κB signaling downregulation partly via cholinergic anti-inflammatory mechanisms.

Uncontrolled inflammatory responses exacerbate the pathogenesis of septic acute liver injury (ALI), posing a lethal threat to the host. Dexmedetomidine (DEX) has been reported to possess protective properties in inflammatory conditions. This study aimed to investigate whether DEX pretreatment exhibits hepatoprotection against ALI induced by lipopolysaccharide (LPS) in rats and determine its possible molecular mechanism. Septic ALI was induced by intravenous injection of LPS. The rats received DEX intraperitoneally 30 min before LPS administration. α-Bungarotoxin (α-BGT), a specific α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, was administered intraperitoneally 1 h before LPS exposure. The role of the vagus nerve was verified by performing unilateral cervical vagotomy or sham surgery before sepsis. The expression of α7nAChR, toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), and cleaved caspase-3 increased, peaking 24 h during sepsis. DEX enhanced α7nAChR activation and reduced TLR4 expression upon challenge with LPS. DEX significantly prevented LPS-induced ALI, which was associated with increased survival, the mitigation of pathological changes, the attenuation of inflammatory cytokine expression and apoptosis, and the downregulation of TLR4/MyD88/NF-κB pathway. Moreover, the hepatoprotective effect of DEX was abolished by α-BGT. Further investigation established that vagotomy, compared to sham surgery, triggered more severe pathogenic manifestations and higher proinflammatory cytokine levels. The inhibitory effects of DEX were shown in sham-operated rats but not in vagotomized rats. Our data highlight the pivotal function of α7nAChR and intact vagus nerves in protecting against LPS-induced ALI through inhibiting the TLR4/MyD88/NF-κB signaling pathway upon pretreatment with DEX.

Zi SF ，Li JH ，Liu L ，Deng C ，Ao X ，Chen DD ，Wu SZ ... -  《-》