Wang Jiaqi, Jiang Yujing, Yuan Yamin, Ma Xin, Li Tongqin, Lv YaTing, Zhang Jing, Chen Liao, Zhou Jinquan, Meng Yanfei, Zhang Bei, Dong Xiaorong, Ma Li
Department of Critical Care Medicine, Lanzhou University Second Hospital, Lanzhou University, Lanzhou City, Gansu Province, People's Republic of China.
Infect Drug Resist. 2025 Jan 9;18:185-197. doi: 10.2147/IDR.S499643. eCollection 2025.
Sepsis is a potentially fatal condition characterized by organ failure resulting from an abnormal host response to infection, often leading to liver and kidney damage. Timely recognition and intervention of these dysfunctions have the potential to significantly reduce sepsis mortality rates. Recent studies have emphasized the critical role of serum exosomes and their miRNA content in mediating sepsis-induced organ dysfunction. The objective of this study is to elucidate the mechanism underlying the impact of miR-122-5p on sepsis-associated liver and kidney injury using inhibitors for miR-122-5p as well as GW4869, an inhibitor targeting exosome release.
Exosomes were isolated from serum samples of septic rats, sepsis patients, and control groups, while liver and kidney tissues were collected for subsequent analysis. The levels of miR-122-5p, inflammation indices, and organ damage were assessed using PCR, ELISA, and pathological identification techniques. Immunohistochemistry and Western blotting methods were employed to investigate the activation of inflammatory pathways. Furthermore, big data analysis was utilized to screen potential targets of miR-122-5p in vivo.
Serum exosomal levels of miR-122-5p were significantly elevated in septic patients as well as in LPS-induced septic rats. Inhibition of miR-122-5p reduced serum pro-inflammatory factors and ameliorated liver and kidney damage in septic rats. Mechanistically, miR-122-5p upregulated TAK1, downregulated SIRT1, and facilitated NF-κB activation.
Serum exosomal miR-122-5p promotes inflammation and induces liver/kidney injury in LPS-induced septic rats by modulating the TAK1/SIRT1/NF-κB pathway, highlighting potential therapeutic targets for sepsis management.
脓毒症是一种潜在的致命病症，其特征是机体对感染的异常反应导致器官功能衰竭，常引发肝损伤和肾损伤。及时识别并干预这些功能障碍有可能显著降低脓毒症死亡率。近期研究强调了血清外泌体及其微小RNA（miRNA）含量在介导脓毒症诱导的器官功能障碍中的关键作用。本研究的目的是使用miR-122-5p抑制剂以及GW4869（一种靶向外泌体释放的抑制剂）来阐明miR-122-5p对脓毒症相关肝损伤和肾损伤影响的潜在机制。
从脓毒症大鼠、脓毒症患者及对照组的血清样本中分离外泌体，同时收集肝组织和肾组织用于后续分析。采用聚合酶链反应（PCR）、酶联免疫吸附测定（ELISA）和病理鉴定技术评估miR-122-5p水平、炎症指标及器官损伤情况。采用免疫组织化学和蛋白质印迹法研究炎症信号通路的激活情况。此外，利用大数据分析筛选miR-122-5p在体内的潜在靶点。
脓毒症患者以及脂多糖（LPS）诱导的脓毒症大鼠血清外泌体中miR-122-5p水平显著升高。抑制miR-122-5p可降低脓毒症大鼠血清促炎因子水平，并改善肝损伤和肾损伤。机制上，miR-122-5p上调转化生长因子激活激酶1（TAK1），下调沉默信息调节因子1（SIRT1），并促进核因子κB（NF-κB）激活。
血清外泌体miR-122-5p通过调节TAK1/SIRT1/NF-κB信号通路促进LPS诱导的脓毒症大鼠炎症反应并导致肝/肾损伤，为脓毒症治疗提供了潜在靶点。
