肌纤维转化生长因子-β信号激活与急性肌损伤炎症反应的相关性研究

目的探讨肢体创伤后急性肌损伤炎症反应过程中肌纤维自身转化生长因子-β(TGF-β)信号对肌内炎症的影响。方法取野生C57BL/6小鼠(野生小鼠组)、肌纤维条件性TGF-β受体Ⅱ敲除小鼠(敲除小鼠组)各16只。肌毒素腓肠肌内注射诱导小鼠急性肌损伤。比较两组小鼠在注射后0、4、7、10 d肌内单核-巨噬细胞、巨噬细胞、M1型巨噬细胞、CD4+T细胞、辅助性T细胞(Th)1、2、17等的渗出差异。取新生野生小鼠和敲除小鼠各2只,体外培养原代成肌细胞,分别分为两组:干扰素组(γ-干扰素处理)和对照组(仅加入等量溶剂)。比较两组肌细胞的白细胞介素(IL)-6、IL-10、单核细胞趋化蛋白1(MCP-1)、巨噬细胞炎症蛋白-1α(MIP-1α)、H-2Kb蛋白、H2-Ea蛋白、Toll样受体(TLR)3蛋白、TLR7蛋白表达差异,以及野生小鼠和敲除小鼠干扰素组之间的差异。结果肌毒素注射后4、7 d,敲除小鼠组肌组织内单核-巨噬细胞比例(75.73%±3.62%、45.27%±2.32%)、巨噬细胞比例(38.67%±2.76%、24.87%±2.19%)、M1型巨噬细胞比例(43.21%±0.11%、30.43%±2.19%)、CD4+T细胞比例(20.13%±1.62%、5.67%±0.32%)显著高于野生小鼠组(58.52%±2.43%、29.21%±2.45%,20.63%±2.32%、16.23%±1.25%,24.98%±0.35%、14.23%±1.69%,10.70%±0.43%、2.50%±0.45%),且以Th1和Th17为主,差异均有统计学意义(P<0.05)。体外实验结果显示:与对照组比较,干扰素组IL-6、MCP-1、MIP-1α、H-2Kb蛋白、H2-Ea蛋白、TLR3蛋白显著上调,且敲除小鼠干扰素组上调较野生小鼠干扰素组更显著,差异均有统计学意义(P<0.05)。结论内源TGF-β信号缺失影响肌纤维免疫行为的调节,使肌内炎症加剧,肌细胞修复延迟。     

牙龈卟啉单胞菌感染对载脂蛋白e基因敲除小鼠动脉粥样硬化的影响

目的: 探讨牙龈卟啉单胞菌(Porphyromonas gingivalis,P. gingivalis)引起的炎症和氧化应激反应对动脉粥样硬化的影响及作用机制。方法: 采用8周龄载脂蛋白e基因敲除(ApoE knockout,ApoE-/-)小鼠建立动脉粥样硬化动物模型,将小鼠随机分为两组:(1)磷酸盐缓冲液(phosphate buffered saline,PBS)健康对照组:8只ApoE-/-小鼠,普通饮食+PBS鼠尾静脉注射;(2)P. gingivalis感染组:8只ApoE-/-小鼠,普通饮食+P. gingivalis鼠尾静脉注射。1周3次,隔天1次,共10次。4周后处死,取心脏组织进行油红O染色,血清进行酶联免疫吸附测定(enzyme-linked immunosorbent assay,ELISA),主动脉进行实时荧光定量PCR以及Western blot检测。结果: P. gingivalis 感染组较PBS健康对照组可以显著加重ApoE-/-小鼠动脉粥样硬化斑块的形成,增加血清中炎症介质,如白细胞介素(interleukin,IL)-1β、IL-6和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)以及氧化应激介质8-羟脱氧鸟苷(8-hydroxy-2-deoxyguanosine,8-OHDG)表达,增加主动脉组织中IL-1β、IL-6、TNF-α、NADPH 氧化酶(NADPH oxidase,NOX)-2和NOX-4基因的mRNA水平。P. gingivalis感染后在主动脉组织中观察到核转录因子-κB(nuclear factor-kappa B,NF-κB)表达有增高趋势。结论: P.gingivalis感染会加速ApoE-/-小鼠动脉粥样硬化进程,诱导氧化应激和炎症反应;NF-κB信号通路可能是P. gingivalis加速动脉粥样硬化形成的重要作用机制。     

Pyroptosis-induced inflammation and tissue damage

Pyroptosis is a programmed necrotic cell death executed by gasdermins, a family of pore-forming proteins. The cleavage of gasdermins by specific proteases enables their pore-forming activity. The activation of the prototype member of the gasdermin family, gasdermin D (GSDMD), is linked to innate immune monitoring by inflammasomes. Additional gasdermins such as GSDMA, GSDMB, GSDMC, and GSDME are activated by inflammasome-independent mechanisms. Pyroptosis is emerging as a key host defense strategy against pathogens. However, excessive pyroptosis causes cytokine storm and detrimental inflammation leading to tissue damage and organ dysfunction. Consequently, dysregulated pyroptotic responses contribute to the pathogenesis of various diseases, including sepsis, atherosclerosis, acute respiratory distress syndrome, and neurodegenerative disorders. This review will discuss the inflammatory consequences of pyroptosis and the mechanisms of pyroptosis-induced tissue damage and disease pathogenesis.