Chen Jingjing, Zhou Lu, Li Mengxin, Wang Jun, Chen Yaru, Xia Jing, Lin Yue, Chen Huizhen, Dong Zibo
Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
Department of Pharmacology, School of Basic Medical Sciences, Kangda College of Nanjing Medical University, Lianyungang 222000, China.
Toxicol Appl Pharmacol. 2025 Nov;504:117540. doi: 10.1016/j.taap.2025.117540. Epub 2025 Aug 31.
Chronic Intermittent Hypoxia (CIH) is a central pathological feature of diseases such as obstructive sleep apnea hypopnea syndrome (OSAHS), which induces oxidative stress in lung tissues and leads to lung injury. Atraric acid (AA), a lichen-derived compound, has been reported to possess anti-inflammatory and antioxidant activities. In this study, we investigated the functions and mechanisms of AA in CIH-induced lung injury by constructing a CIH mouse model and an in vitro hypoxia/reoxygenation model in MLE-12 cells. Various methods were employed, including hematoxylin and eosin (H&E) staining, biochemical assay kits, quantitative polymerase chain reaction (qPCR) analysis, protein blotting, immunofluorescence, and flow cytometry. The results showed that AA pretreatment significantly attenuated pathological injury of mouse lung tissue, reduced pulmonary edema, reactive oxygen species (ROS) and malondialdehyde production, as well as the depletion of total antioxidant capacity, catalase and glutathione, and lowered the expression levels of inflammatory factors. Mechanistic studies showed that AA up-regulated solute transport family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression and down-regulated prostaglandin-endoperoxide synthase 2 (PTGS2) through activation of the Nrf2 signaling pathway, whereas the Nrf2 inhibitor ML385 completely blocked this protective effect. In conclusion, the present study demonstrates that AA targets the Nrf2 axis, attenuated CIH-induced inflammation, alleviates ROS accumulation, and blocks the vicious cycle of oxidative stress, ferroptosis, and inflammation, making it a promising therapeutic strategy for the treatment of CIH-induced lung injury.
慢性间歇性缺氧（CIH）是阻塞性睡眠呼吸暂停低通气综合征（OSAHS）等疾病的核心病理特征，其可诱导肺组织氧化应激并导致肺损伤。阿特拉酸（AA）是一种地衣衍生化合物，据报道具有抗炎和抗氧化活性。在本研究中，我们通过构建CIH小鼠模型和MLE-12细胞体外缺氧/复氧模型，研究了AA在CIH诱导的肺损伤中的作用及其机制。采用了多种方法，包括苏木精和伊红（H&E）染色、生化检测试剂盒、定量聚合酶链反应（qPCR）分析、蛋白质印迹、免疫荧光和流式细胞术。结果表明，AA预处理可显著减轻小鼠肺组织的病理损伤，减少肺水肿、活性氧（ROS）和丙二醛生成，以及总抗氧化能力、过氧化氢酶和谷胱甘肽的消耗，并降低炎症因子的表达水平。机制研究表明，AA通过激活Nrf2信号通路上调溶质转运家族7成员11（SLC7A11）和谷胱甘肽过氧化物酶4（GPX4）的表达，并下调前列腺素内过氧化物合酶2（PTGS2），而Nrf2抑制剂ML385完全阻断了这种保护作用。总之，本研究表明，AA靶向Nrf2轴，减轻CIH诱导的炎症，减轻ROS积累，并阻断氧化应激、铁死亡和炎症的恶性循环，使其成为治疗CIH诱导的肺损伤的一种有前景的治疗策略。
