Guo Jianning, Qu Xiaoxuan, Ge Ruidong, Liu Die, Liu Jing, Hui Qin, Ye Fang, Chen Yuanmei, Wang Chao, Lv Di, Tang Lijuan, Xia Meihong, Zhang Qi
Department of Pediatrics, China-Japan Friendship Hospital, Beijing, China.
Department of Rehabilitation Medicine, China-Japan Friendship Hospital, Beijing, China.
Front Immunol. 2025 Aug 21;16:1637378. doi: 10.3389/fimmu.2025.1637378. eCollection 2025.
The pathological mechanism of sepsis-related acute lung injury (ALI) is closely linked to mitochondrial dysfunction and pyroptosis. Although low-dose extracorporeal shock wave (SW) therapy has been widely utilized in tissue and organ injury repair, its role in sepsis-related ALI remains unclear. This study aimed to elucidate the regulatory mechanisms of SW on mitochondrial pyroptosis crosstalk in septic ALI.
The sepsis-related ALI mouse model was induced by tail vein injection of LPS. , LPS and ATP induced a pyroptosis model in type II alveolar epithelial (AT2) cells. The levels of inflammatory factors and oxidative stress were detected. The ultrastructure of lung mitochondria was observed by transmission electron microscope. Moreover, the mitochondrial membrane potential, ATP content, and the level of mtDNA were determined in cells and tissues. Western blot was used to detect mitochondrial oxidative stress and dysfunction, as well as the expression of pyroptosis-related proteins mediated by NLRP3 inflammasome.
SW significantly reduced the secretion levels of inflammatory factors TNF-α, IL-1β, IL-6, and IL-8 in serum, alveolar lavage fluid (BALF), and cell supernatant, inhibited oxidative stress markers (ROS, MDA, MPO), and upregulated antioxidant index (SOD, GSH). Pathological evidence indicates that SW can alleviate the pathological changes of lung injury and restore the mitochondrial ultrastructure of AT2 cells. The mechanism study shows that SW can enhance mitochondrial membrane potential and ATP production, inhibit mtDNA migration and p65 nuclear translocation, and down-regulate the expression of mitochondrial coding genes (MT-ND2, MT-ND4) and iNOS. At the same time, SW inhibited the NLRP3/ASC/Caspase-1 signaling axis, thereby disrupting pyroptosis cascades.
This study reveals that SW attenuates septic ALI by targeting mitochondrial-pyroptosis crosstalk, offering a novel non-invasive therapeutic strategy for clinical applications.
脓毒症相关急性肺损伤（ALI）的病理机制与线粒体功能障碍和细胞焦亡密切相关。尽管低剂量体外冲击波（SW）疗法已广泛应用于组织和器官损伤修复，但其在脓毒症相关ALI中的作用仍不清楚。本研究旨在阐明SW对脓毒症ALI中线粒体细胞焦亡串扰的调控机制。
通过尾静脉注射脂多糖（LPS）诱导脓毒症相关ALI小鼠模型。LPS和ATP诱导II型肺泡上皮（AT2）细胞焦亡模型。检测炎症因子和氧化应激水平。通过透射电子显微镜观察肺线粒体超微结构。此外，测定细胞和组织中的线粒体膜电位、ATP含量和线粒体DNA水平。采用蛋白质免疫印迹法检测线粒体氧化应激和功能障碍，以及由NLRP3炎性小体介导的细胞焦亡相关蛋白的表达。
SW显著降低血清、肺泡灌洗液（BALF）和细胞上清液中炎症因子TNF-α、IL-1β、IL-6和IL-8的分泌水平，抑制氧化应激标志物（ROS、MDA、MPO），并上调抗氧化指标（SOD、GSH）。病理证据表明，SW可减轻肺损伤的病理变化，恢复AT2细胞的线粒体超微结构。机制研究表明，SW可增强线粒体膜电位和ATP生成，抑制线粒体DNA迁移和p65核转位，并下调线粒体编码基因（MT-ND2、MT-ND4）和诱导型一氧化氮合酶（iNOS）的表达。同时，SW抑制NLRP3/凋亡相关斑点样蛋白（ASC）/半胱天冬酶-1信号轴，从而破坏细胞焦亡级联反应。
本研究表明，SW通过靶向线粒体-细胞焦亡串扰减轻脓毒症ALI，为临床应用提供了一种新的非侵入性治疗策略。
