谈剑.SRT2104通过调控p53/NF-κB信号轴改善急性胰腺炎相关急性肺损伤[J].内科急危重症杂志,2025,31(1):77-82
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| DOI：10.11768/nkjwzzzz20250115 |
| 中文关键词: SRT2104 p53/NF κB 急性胰腺炎 急性肺损伤 |
| 英文关键词: |
| 基金项目:江苏省卫生健康委员会科研项目（F2020072） |
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| 中文摘要: |
| 摘要 目的：探讨小分子Sirtuin1激活剂（SRT2104）改善急性胰腺炎（AP）相关急性肺损伤（ALI）的作用机制。方法：选取24只BALB/c小鼠随机分为3组：对照组、AP组和AP+SRT2104组，每组8只。AP组和AP+SRT2104组通过腹腔注射雨蛙素和脂多糖诱导AP-ALI模型，AP+SRT2104组在AP诱导前腹腔注射SRT2104（25mg/kg）。对小鼠模型进行胰腺、肺组织病理学分析，测量血清淀粉酶水平及肺干湿重比。测定小鼠支气管肺泡灌洗液蛋白浓度、伊文思蓝渗出和肺微血管内皮细胞超微结构变化。通过TUNEL实验，判断小鼠肺细胞凋亡情况。蛋白免疫印迹法检测小鼠肺组织匀浆细胞中p53和NF-κB、IKBα、PP65 S529、SIRT1的蛋白水平。将人肺微血管内皮细胞（HPMECs）暴露于不同浓度的肿瘤坏死因子-α(TNF-α）刺激剂下模拟HPMECs损伤，通过CCK8测定细胞活力，蛋白免疫印迹法检测细胞凋亡蛋白表达。结果：AP+SRT2104组小鼠的淀粉酶水平、胰腺和肺的组织病理学损伤评分和肺湿/干重比显著低于AP组（P均<0.05）。与AP组比较，AP+SRT2104组小鼠的肺泡灌洗液蛋白浓度、伊文思蓝在肺组织中的累积和肺组织中凋亡细胞显著降低（P均<0.05），肺内皮细胞肿胀和损伤部分减轻，并且p53、NF-κB蛋白表达显著降低（P均<0.05）。在体外细胞系实验中，SRT2104处理组HPMECs的细胞活力和存活率显著提高（P<0.05）。结论：SRT2104可能通过抑制p53/NF-κB信号通路防止细胞凋亡，从而减弱AP诱导的ALI反应。 |
| 英文摘要: |
| Abstract Object: To investigate the mechanism of SRT2104 in ameliorating acute lung injury (ALI) associated with acute pancreatitis (AP). Methods: BALB/c mice were randomly divided into three experimental groups: control group, AP group, and AP+SRT2104 group, with 8 mice in each group. AP group and AP+SRT2104 group were induced with AP-ALI model by intraperitoneal injection of cerulein and lipopolysaccharide. In the AP+SRT2104 group, SRT2104 (25mg/kg) was injected intraperitoneally before AP induction. The pathological changes in pancreatic and lung tissue were examined, serum amylase levels were determined, and lung wet-to-dry weight ratio were analyzed to assess the extent of AP-ALI damage in mouse models. Bronchoalveolar lavage fluid protein concentration, Evans blue extravasation, and changes in lung microvascular endothelial cell ultrastructure were measured to determine lung microvascular permeability. TUNEL assay was performed to assess lung cell apoptosis. Western blotting was used to measure the protein levels of p53, NF-κB, p53, IKBα, PP65 S529 and SIRT1in mouse lung tissue homogenates to further evaluate the potential mechanisms of SRT2104 protection. In vitro cell experiments, human pulmonary microvascular endothelial cells (HPMECs) were exposed to different concentrations of TNF-α to simulate HPMECs injury, and cell viability was determined by CCK8 assay with or without SRT2104 treatment , and Western blotting was performed to detect cell apoptosis and protein expression. Results: The levels of amylase, pancreatic and lung tissue pathology scores, and lung wet-to-dry weight ratio in the AP+SRT2104 group were significantly lower than in the AP group (P <0.05). Compared with the AP group, the protein concentration in bronchoalveolar lavage fluid, accumulation of Evans blue in lung tissue, and apoptosis cells in lung tissue were significantly reduced in the AP+SRT2104 group (P< 0.05), and endothelial cell swelling and damage were alleviated, and the protein expression of p53/NF-κB was significantly decreased (P< 0.05). In the in vitro cell experiments, compared with the TNF-α-stimulated group without SRT2104 treatment, the cell viability and survival rate of HPMECs in the SRT2104-treated group were significantly increased (P< 0.05). Conclusion: SRT2104 may attenuate AP-induced ALI by inhibiting p53/NF-κB signaling pathway activation to prevent cell apoptosis. |
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