Effects of Caspase⁃1⁃mediated pyroptosison on neuronal injury in sepsis mice
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摘要:
目的：观察半胱氨酸蛋白酶-1（Caspase-1）介导的焦亡在脓毒症小鼠神经元损伤中的作用。方法：盲肠结扎穿孔法（cecal ligation and puncture，CLP）建立小鼠脓毒症模型。成年雄性C57BL/6小鼠90只随机分为4组：假手术+生理盐水组（Sham组，15只）、假手术+Caspase-1特异性抑制剂Ac-YVAD-CMK组（Sham+CMK组，15只）、脓毒症+生理盐水组（CLP组，30只）和脓毒症+Ac-YVAD-CMK组（CLP+CMK组，30只），术后第7天各组取6只小鼠分离脑组织，检测海马CA1区神经元损伤情况和Caspase-1阳性细胞数，以及海马组织Caspase-1、焦亡标记物Gasdermin-D蛋白（GSDMD）、白细胞介素（interleukin，IL）-1β和IL-18水平；余下小鼠术后第14天行条件恐惧性实验检测认知功能。结果：与Sham组相比，CLP组小鼠海马CA1区神经元明显损伤，Caspase-1阳性细胞数增多，海马组织中Caspase-1、GSDMD、IL-1β及IL-18含量明显升高（P < 0.05），表现为海马依赖的认知功能损伤。与CLP组相比，CLP+CMK组小鼠CA1区神经元无明显损伤，Caspase-1阳性细胞数减少，Caspase-1、GSDMD、IL-1β及IL-18含量降低，认知功能明显改善（P < 0.05）。结论：脓毒症可引起小鼠海马神经元损伤及Caspase-1介导的焦亡的激活，抑制Caspase-1介导的焦亡具有神经元保护和认知保护作用。
Abstract:
Objective：To observe the effects of Caspase-1-mediated pyroptosis on neuronal injury in sepsis mice. Methods：Mouse model of sepsis was established by cecal ligation and puncture（CLP）surgery. Ninety adult male C57BL/6 mice were randomly divided into four groups：Sham+saline group（n=15，Sham group），Sham + Caspase-1 inhibitorAc-YVAD-CMKgroup（N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone，n=15，Sham+CMK group），CLP + saline group（n=30，CLP group）and CLP+Ac-YVAD-CMK group（n=30，CLP+CMK group）. Seven days after surgery，the brain of each mouse（n=6/each group）was rapidly harvested for determiningthescore of neuronal injury，number of Caspase-1-immunoreactive cells，contents of cleaved Caspase-1，pyroptosisbiomarker Gasdermin-D（GSDMD），interleukin-1β（IL-1β）and IL-18. Fourteen days after surgery，fear conditioning test was performed to evaluate the cognitive function for the rest of the mice. Results：Compared with the Sham group，the score of neuronal damage，number of Caspase-1-immunoreactive cells，contents of cleaved Caspase-1，GSDMD，IL-1β and IL-18 were significantly increased in the CLP group（P < 0.05），and mice of CLP group exhibited significant hippocampus-dependent cognitive impairment. Compared with the CLP group，increase of Caspase-1，GSDMD，IL-1β and IL-1β were inhibited by Ac-YVAD-CMK administration in the CLP+CMK group（P < 0.05）. Conclusion：Sepsis induces neuronal injury and activation of Caspase-1-mediated pyroptosis in mice hippocampus，and inhibiting Caspase-1 with Ac-YVAD-CMK ameliorates sepsis-induced pyroptosis，neuronal injury and cognitive impairment.
