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瑞马唑仑通过调节HMGB1/RAGE/NF-κB信号通路抑制大鼠视网膜缺血再灌注损伤

Remimazolam inhibits retinal ischemia/reperfusion injury in rats by modulating the HMGB1/RAGE/NF-κB signaling pathway

    摘要
  • 摘要:
    目的  探究瑞马唑仑（Rem）对大鼠视网膜缺血再灌注损伤（RIRI）的抑制作用以及对高迁移率族蛋白B1/晚期糖基化终末产物受体/核转录因子-κB（HMGB1/RAGE/NF-κB）信号通路的调节机制。
    方法  将大鼠随机分为假手术组（Sham组）、模型组（Model组）、低剂量Rem（Rem-L）组、中剂量Rem（Rem-M）组、高剂量Rem（Rem-H）组和高剂量Rem+HMGB1激活剂DEX（Rem-H+DEX）组。除Sham组外均采用升高眼压的方式构建RIRI大鼠模型。采用HE染色检测视网膜组织结构变化；采用TUNEL染色观察视网膜组织细胞凋亡；采用酶联免疫吸附（ELISA）法检测各组大鼠血清白细胞介素1β（IL-1β）、肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）表达水平；采用试剂盒检测氧化应激指标超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-PX）和丙二醛（MDA）的水平；采用蛋白免疫印迹（Western blot）法检测视网膜组织中缺氧相关因子缺氧诱导因子-1α（HIF-1α），血管内皮生长因子（VEGF）以及HMGB1/RAGE/NF-κB信号通路相关蛋白表达水平。
    结果  Model组大鼠相较于Sham组，其视网膜呈高度水肿，神经节细胞数目明显减少，细胞出现空泡样变化，且排列紊乱，细胞间隙增宽，而随着Rem注射剂量的增加，大鼠视网膜水肿程度逐渐减轻，且神经节细胞数量增多，排列逐渐趋于有序；相较于Sham组，Model组大鼠视网膜细胞凋亡率，血清IL-1β，IL-6，TNF-α以及视网膜组织中MDA，HMGB1，RAGE，NF-κB，HIF-1α，VEGF表达水平均升高（P＜0.05），而SOD，GSH-PX表达水平降低（P＜0.05）；相较于Model组，Rem-L组、Rem-M组和Rem-H组大鼠视网膜细胞凋亡率，血清IL-1β，IL-6，TNF-α以及视网膜组织中MDA，HMGB1，RAGE，NF-κB，HIF-1α，VEGF表达水平逐渐降低（P＜0.05），SOD、GSH-PX表达水平逐渐升高（P＜0.05），上述指标变化均呈剂量依赖性；HMGB1激活剂DEX的加入逆转了上述指标的变化趋势。
    结论  Rem能够抑制大鼠RIRI，其作用机制可能与抑制HMGB1/RAGE/NF-κB信号通路有关。

     

    Abstract:
    Objective  To investigate the inhibitory effect of remimazolam (Rem) on retinal ischemia/reperfusion injury (RIRI) and the regulatory mechanism on high mobility group protein B1/receptor for advanced glycation end product/nuclear transcription factor-κB (HMGB1/RAGE/NF-κB) signaling pathway in rats.
    Methods  Randomly divide rats into sham surgery group (Sham group), model group, low-dose Rem (Rem-L) group, medium-dose Rem (Rem-M) group, high-dose Rem (Rem-H) group and high-dose Rem+HMGB1 activator DEX (Rem-H+DEX) group. Except for the Sham group, the RIRI rat model was constructed by increasing intraocular pressure. HE staining was used to detect the structural changes of retinal tissue. TUNEL staining was used to observe retinal histiocyte apoptosis. Enzyme-linked immunosorbent disease (ELISA) was used to detect the expression levels of serum interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) in each group. The levels of SOD, GSH-PX and MDA were detected by the kits. Western blot was used to detect the expression levels of hypoxia-related factors hypoxia-inducible factor-1α (HIF-1α), VEGF and HMGB1/RAGE/NF-κB signaling pathway-related proteins in retinal tissue.
    Results  Compared with the Sham group, the retina of the Model group was highly edema, the number of ganglion cells was greatly reduced, the cells showed vacuole-like changes, and the arrangement was disordered, and the intercellular space was widened. While with the increase of Rem injection dose, the degree of retinal edema of the rats gradually decreased, and the number of ganglion cells increased, and the arrangement gradually became orderly. Compared with the Sham group, the apoptosis rate of retinal cells, serum IL-1β, IL-6, TNF-α and the expression levels of MDA, HMGB1, RAGE, NF-κB, HIF-1α and VEGF in retinal tissues in the Model group increased (P<0.05), the expression levels of SOD and GSH-PX decreased (P<0.05). Compared with the model group, the apoptosis rate of retinal cells, serum IL-1β, IL-6, TNF-α and the expression levels of MDA, HMGB1, RAGE, NF-κB, HIF-1α and VEGF in retinal tissues in the Rem-L group, Rem-M group and Rem-H group decreased gradually (P<0.05), the expression levels of SOD and GSH-PX increased gradually (P<0.05), the changes in the above indicators are dose-dependent; The addition of the HMGB1 activator DEX reversed the trend of the above indicators.
    Conclusion  Rem can inhibit rat RIRI, and its mechanism of action may be related to the inhibition of HMGB1/RAGE/NF-κB signaling pathway.

     

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