SOD1-PRDX2-TXN轴通过协同抗氧化活性保护慢性鼻窦炎中的鼻上皮屏障

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中文摘要

目的： 探讨SOD1-PRDX2-TXN轴在调节慢性鼻窦炎（CRS）鼻上皮屏障功能中的作用。
方法： 采用生物信息学分析鉴定CRS相关的线粒体功能基因。使用脂多糖（LPS）建立体外和体内CRS模型。通过过表达/敲低SOD1/PRDX2/TXN，并结合氧化应激诱导剂（H₂O₂），通过H&E/PAS/TUNEL/JC-1染色、TEER/通透性检测、免疫荧光、免疫组织化学、ELISA、Co-IP和ROS检测评估鼻上皮屏障功能、氧化应激、线粒体功能和蛋白质-蛋白质相互作用。此外，我们在公共临床转录组数据集（GSE36830）中分析了SOD1、PRDX2和TXN的表达。
结果： SOD1和PRDX2被鉴定为核心线粒体功能基因，二者在CRS模型中均下调，并与屏障损伤相关。在临床数据集GSE36830中，SOD1和PRDX2在CRS患者中的表达显著下调。SOD1过表达降低了ROS/MDA，增加了SOD活性，改善了TEER，降低了通透性，恢复了紧密连接蛋白表达，并减少了细胞凋亡。H₂O₂部分逆转了这些效应。PRDX2敲低消除了SOD1的保护作用，增加了ROS/MDA，降低了线粒体膜电位，并恶化了屏障功能。在CRS小鼠模型中SOD1活性降低，并可通过SOD1过表达恢复，而PRDX2敲低降低了SOD1活性。Co-IP证实了SOD1-PRDX2和PRDX2-TXN之间的相互作用。PRDX2过表达部分恢复了LPS诱导的TXN下调。在PRDX2敲低细胞中，TXN过表达恢复了SOD1、PRDX2和TXN水平，进一步降低了ROS、MDA和4-HNE，并改善了屏障功能。在体内，TXN过表达减少了炎症浸润、杯状细胞增生和IL-6/IL-18/TNF-α水平，同时增强了抗氧化能力和屏障完整性。Co-IP证实了体内SOD1、PRDX2和TXN之间复合物的形成。
结论： SOD1、PRDX2和TXN可能形成一个功能性抗氧化酶链，通过协同减少氧化应激、保护线粒体功能和维持紧密连接完整性来保护CRS中的鼻上皮屏障。靶向该轴可能为CRS提供一种新的抗氧化治疗策略。

英文摘要

OBJECTIVE: To explore the role of the SOD1-PRDX2-TXN axis in regulating nasal epithelial barrier function in chronic rhinosinusitis (CRS).
METHODS: Bioinformatic analysis was used to identify CRS-associated mitochondrial function genes. In vitro and in vivo CRS models were established using lipopolysaccharide (LPS). Through overexpression/knockdown of SOD1/PRDX2/TXN, combined with an oxidative stress inducer (H₂O₂), nasal epithelial barrier function, oxidative stress, mitochondrial function, and protein-protein interactions were assessed via H&E/PAS/TUNEL/JC-1 staining, TEER/permeability assays, immunofluorescence, immunohistochemistry, ELISA, Co-IP, and ROS detection. Additionally, we analyzed the expression of SOD1, PRDX2, and TXN in a public clinical transcriptomic dataset (GSE36830).
RESULTS: SOD1 and PRDX2 were identified as core mitochondrial function genes, both downregulated in CRS models, correlating with barrier impairment. In the clinical dataset GSE36830, SOD1 and PRDX2 expression was significantly downregulated in CRS patients. SOD1 overexpression reduced ROS/MDA, increased SOD activity, improved TEER, reduced permeability, restored tight junction protein expression, and decreased apoptosis. H₂O₂ partially reversed these effects. PRDX2 knockdown abolished SOD1's protective effects, increasing ROS/MDA, reducing mitochondrial membrane potential, and worsening barrier function. SOD1 activity was decreased in the CRS mouse model and was restored by SOD1 overexpression, while PRDX2 knockdown reduced SOD1 activity. Co-IP confirmed interactions between SOD1-PRDX2 and PRDX2-TXN. PRDX2 overexpression partially restored LPS-induced TXN downregulation. In PRDX2-knockdown cells, TXN overexpression restored SOD1, PRDX2, and TXN levels, further reduced ROS, MDA, and 4-HNE, and improved barrier function. In vivo, TXN overexpression reduced inflammatory infiltration, goblet cell hyperplasia, and IL-6/IL-18/TNF-α levels, while enhancing antioxidant capacity and barrier integrity. Co-IP confirmed in vivo complex formation among SOD1, PRDX2, and TXN.
CONCLUSION: SOD1, PRDX2, and TXN may form a functional antioxidant enzyme chain that protects the nasal epithelial barrier in CRS by synergistically reducing oxidative stress, preserving mitochondrial function, and maintaining tight junction integrity. Targeting this axis could offer a new antioxidant therapy strategy for CRS.