Department of Critical Care Medicine, Affiliated Haikou Hospital, Xiangya School of Medicine, Central South University, Haikou 570208, China.
Department of Critical Care Medicine, Affiliated Haikou Hospital, Xiangya School of Medicine, Central South University, Haikou 570208, China.
Int Immunopharmacol. 2019 Nov;76:105898. doi: 10.1016/j.intimp.2019.105898. Epub 2019 Sep 11.
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.
失控的炎症反应会加重脓毒症急性肝损伤（ALI）的发病机制，对宿主构成致命威胁。右美托咪定（DEX）已被报道在炎症情况下具有保护作用。本研究旨在探讨 DEX 预处理是否对 LPS 诱导的大鼠 ALI 具有肝保护作用，并确定其可能的分子机制。
通过静脉注射 LPS 诱导脓毒症性 ALI。大鼠在 LPS 给药前 30min 腹腔内给予 DEX。在 LPS 暴露前 1h 腹腔内给予α-银环蛇毒素（α-BGT），一种特异性α7 烟碱型乙酰胆碱受体（α7nAChR）拮抗剂。在脓毒症前通过单侧颈迷走神经切断术或假手术验证迷走神经的作用。
α7nAChR、Toll 样受体 4（TLR4）、高迁移率族蛋白 1（HMGB1）和 cleaved caspase-3 的表达在脓毒症期间增加，24h 时达到峰值。DEX 增强了 LPS 刺激时的α7nAChR 激活，并降低了 TLR4 的表达。DEX 显著预防了 LPS 诱导的 ALI，提高了生存率，减轻了病理变化，减轻了炎症细胞因子的表达和凋亡，并下调了 TLR4/MyD88/NF-κB 通路。此外，α-BGT 消除了 DEX 的肝保护作用。进一步的研究表明，与假手术相比，迷走神经切断术导致更严重的发病表现和更高的促炎细胞因子水平。DEX 的抑制作用在假手术大鼠中表现出来，但在迷走神经切断术大鼠中没有表现出来。
我们的数据强调了 α7nAChR 和完整的迷走神经在通过抑制 TLR4/MyD88/NF-κB 信号通路在 DEX 预处理中防止 LPS 诱导的 ALI 中的关键作用。
