机械敏感离子通道Piezo1调控鼠疟模型肝损伤的作用研究  

Role of mechanosensitive ion channel Piezo1 in mediating the severity of experimental malaria-associated lung injury

作　　者：刘嘉慧 张敏 邢广科 刘一然 侯信鹏 莫秀梅 何家靖 金小宝 黄博 LIU Jiahui;ZHANG Min;XING Guangke;LIU Yiran;HOU Xinpeng;MO Xiumei;HE Jiajing;JIN Xiaobao;HUANG Bo(Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances,Guangzhou 510006,China;Department of Medical laboratory,The Second Affiliated Hospital of Guangdong Medical University,Zhanjiang 514021,China;Experimental Animal Center,Guangdong Pharmaceutical University,Guangzhou 510006,China;School of Basic Medical Science,Guangdong Pharmaceutical University,Guangzhou 510006,China)

机构地区：[1]广东省生物活性药物研究重点实验室,广东广州510006 [2]广东医科大学附属第二医院检验医学科,广东湛江514021 [3]广东药科大学实验动物中心,广东广州510006 [4]广东药科大学基础医学院,广东广州510006

出　　处：《广东药科大学学报》2025年第1期8-15,共8页Journal of Guangdong Pharmaceutical University

基　　金：广东药科大学大学生创新创业训练计划项目(202210573068、202310573072);广东省中医药局中医药科研项目(20231207);广东省医学科研基金项目(A2023240、A2024384)。

摘　　要：目的探讨机械敏感离子通道1(Piezo1)活性抑制剂GsMTx4蜘蛛毒素肽(GsMTx4)对感染伯氏疟原虫安卡株(Plasmodium berghei ANKA)小鼠肝损伤的影响及其潜在作用机制。方法48只雌性C57BL/6小鼠随机分为4组:正常对照组(Control组)8只、Piezo1抑制剂-蜘蛛毒液肽4组(GsMTx4组)8只、感染组(Pb组)16只和感染+蜘蛛毒液肽4组(Pb+GsMTx4组)16只。吉姆萨染色和qPCR法检测各组小鼠红细胞原虫感染率和肝组织虫荷变化,苏木素-伊红染色分析各组小鼠肝组织病理学改变,普鲁士蓝染色观察铁含量,以及免疫组织化学检测巨噬细胞的标识物(CD68)、M1型巨噬细胞的标识物(CD86)、Piezo1、抑制铁死亡的关键分子(GPX4)和启动铁死亡的关键分子(4-羟基壬烯醛,4-HNE)的表达情况。结果P.berghei ANKA感染后,Pb组小鼠肝组织的铁蓄积水平和Piezo1表达均显著升高,伴随着显著的肝组织病理损伤。与Pb组相比,GsMTx4处理显著降低感染小鼠的铁积蓄水平、红细胞原虫感染率、虫荷和肝组织病理损伤,显著下调巨噬细胞标记物CD68、M1型巨噬细胞标志物CD86、Piezo1和4-HNE的表达,显著上调谷胱甘肽过氧化物酶4(GPX4)表达。结论Piezo1活性抑制剂GsMTx4减轻鼠疟肝损伤,其作用机制可能与调节巨噬细胞M1极化和铁死亡有关。Objective To investigate the effect of mechanosensitive ion channel Piezo1 inhibitor(GsMTx4)on liver injury of Plasmodium berghei ANKA-infected mice.Methods Forty-eight female C57BL/6 mice were randomly assigned to four groups,including the control group(n=8),GsMTx4 group(n=8),Pb group(n=16),and the Pb+GsMTx4 group(n=16).Peripheral parasitemia or liver parasite burden(P.berghei ANKA 18S rRNA)was determined using Giemsa-stained thin blood smears or qPCR assay.H&E staining was employed to evaluate pathological changes,while Prussian blue staining was taken to assess iron content in liver tissues.Additionally,immunohistochemistry was performed to detect the protein expressions of CD68(a marker for macrophages),CD86(a marker for M1-subtype macrophages),Piezo1,GPX4(an inhibitor of ferroptosis),and 4-HNE(an activator of ferroptosis) in liver tissues. Results Following P. berghei ANKA infection, the animals at Pb groupdisplayed a dramatic elevation in iron accumulation and Piezo1 expression on the liver tissues, followed by theobvious liver pathological damage. Compared to Pb group, treatment of Piezo1 inhibitor (GsMTx4) on theinfected mice dramatically decreased iron accumulation, peripheral blood parasitemia, liver parasite burden andpathological damage. Notably, administration of GsMTx4 also led to a substantial decline in the numbers of CD68and CD86, protein expression of Piezo1 and 4-HNE, but triggered a notable elevation in GPX4 expression in theliver tissue from Pb+GsMTx4 group. Conclusion Blockage of Piezo1 with GsMTx4 alleviated liver injury of P.berghei ANKA-infected mice by partially reducing ferroptosis and inhibiting macrophage M1 polarization.

关 键 词：伯氏疟原虫 肝脏 Piezo1 铁死亡 巨噬细胞 

分 类 号：R965[医药卫生—药理学]