| 分子伴侣介导的自噬在重症急性胰腺炎相关肝损伤中的作用及其机制 |
| 投稿时间：2024-09-29 修订日期：2024-12-02 点此下载全文 |
| 引用本文：李忠标,杜敏,王江,于跃,赵习浩,张佃良.分子伴侣介导的自噬在重症急性胰腺炎相关肝损伤中的作用及其机制[J].医学研究杂志,2025,54(4):39-44 |
| DOI：
10.11969/j.issn.1673-548X.2025.04.009 |
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| 基金项目:国家自然科学基金资助项目(面上项目)(81270448,81470890) |
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| 中文摘要:目的 急性肝损伤(acute liver injury, ALI)会加剧重症急性胰腺炎(severe acute pancreatitis, SAP)患者的病情,并对其预后产生不良影响。近年来研究强调了分子伴侣介导的自噬(chaperone-mediated autophagy, CMA)在调控肝损伤中的重要作用。本研究旨在探讨CMA在SAP相关肝损伤(SAP-associated liver injury, SAP-ALI)病理机制中的作用。方法 通过胆胰管逆行注入5%牛磺胆酸钠建立SAP大鼠模型。大鼠被随机分为假手术(Sham)组、SAP组、CMA激活剂(AR7)对照组和CMA激活剂(AR7)+SAP治疗组。24h后,检测各组大鼠的血清淀粉酶(serum amylase,AMY)、肝功能以及氧化应激特异性指标；通过HE染色评估胰腺和肝组织的病理学变化；并通过Western blot法检测、免疫荧光染色和qRT-PCR技术分析溶酶体相关膜蛋白2A(lysosomal-associated membrane protein 2A, LAMP2A)、GAPDH、Kelch样环氧氯丙烷相关蛋白1(keleh-like ECH-associated protein 1,Keap1)和核因子E2相关因子2(nuclear factor E2-related factor 2,Nrf2)蛋白表达以及LAMP2A和Nrf2mRNA表达。结果AR7预处理显著恢复了SAP大鼠的肝功能(P<0.05),减轻了胰腺和肝组织的病理损伤,增强了肝脏的抗氧化应激能力(P<0.05)。在SAP诱导的急性肝损伤中,LAMP2A表达下调(P<0.05)及CMA底物GAPDH的积累(P<0.05)提示CMA功能障碍。此外,AR7诱导的CMA上调,促进了SAP大鼠肝脏Keap1/Nrf2通路的活化(P<0.05),从而发挥其抗氧化作用。结论 本研究结果表明,CMA失调参与了SAP相关急性肝损伤的病理过程,AR7诱导的CMA再激活能够上调Keap1/Nrf2抗氧化通路,改善大鼠SAP诱导的急性肝损伤。 |
| 中文关键词:分子伴侣介导的自噬 氧化应激 Nrf2 急性肝损伤 重症急性胰腺炎 |
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| Effects and Mechanism of Chaperone-Mediated Autophagy on Severe Acute Pancreatitis-Associated Liver Injury. |
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| Abstract:Objective Acute liver injury (ALI) exacerbates the condition of patients with severe acute pancreatitis (SAP) and negatively affects their prognosis. Recent studies have highlighted the crucial role of chaperone-mediated autophagy (CMA) in regulating liver injury. This study aims to explore the effects of CMA on the pathophysiologic mechanisms of SAP-induced acute liver injury (SAP-ALI). Methods A SAP rat model was established via retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct. Rats were randomly divided into the sham operation (Sham) group, SAP group, CMA activator (AR7) control group, and AR7+SAP treatment group. After 24hours, serum amylase (AMY), liver function, and oxidative stress-specific markers were measured. HE staining was used to evaluate the pathological injury in the pancreatic and liver tissues. The expression levels of lysosomal-associated membrane protein 2A (LAMP2A), GAPDH, keleh-like ECH-associated protein 1 (Keap1), and nuclear factor E2-related factor 2 (Nrf2) proteins and LAMP2A, Nrf2mRNA were analyzed by Western blot, immunofluorescence staining, and qRT-PCR. Results AR7 pretreatment significantly improved liver function (P<0.05), alleviated the pathological damage to the pancreas and liver and enhanced the antioxidant stress capacity (P<0.05) of SAP-ALI rats. The downregulation of LAMP2A (P<0.05) and accumulation of the CMA substrate GAPDH (P<0.05) indicated CMA dysfunction in SAP-ALI. Furthermore, AR7-induced upregulation of CMA promoted the activation of the Keap1/Nrf2 pathway in liver(P<0.05), contributing to its antioxidative effect. Conclusion Our study demonstrates that CMA dysfunction is involved in the pathological process of SAP-induced acute liver injury. AR7-induced CMA reactivation regulates the Keap1/Nrf2 antioxidant pathway, providing protection against SAP-induced acute liver injury in rats. |
| keywords:CMA Oxidative stress Nrf2 Acute liver injury Severe acute pancreatitis |
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