Caspase⁃1介导的焦亡在脓毒症小鼠神经元损伤中的作用研究
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安徽省高校自然科学研究重点项目(KJ2016A730)


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.

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尹 磊,傅 群,石金云,吴 晶,吴敬医. Caspase⁃1介导的焦亡在脓毒症小鼠神经元损伤中的作用研究[J].南京医科大学学报(自然科学版),2019,(11):1567-1570

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  • 收稿日期:2018-09-27
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  • 在线发布日期: 2019-12-02
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