Wang Jiajia, Gao Jinhui, Ding Ling, Yang Xuanzhe, Zheng Dong, Zeng Yuanyuan, Zhu Jianjie, Lei Wei, Chen Cheng, Liu Zeyi, Huang Jian-An
Department of Pulmonary and Critical Care Medicine and.
Institute of Respiratory Diseases and.
Am J Respir Cell Mol Biol. 2025 Feb;72(2):181-194. doi: 10.1165/rcmb.2024-0067OC.
The role of circular RNAs (circRNAs) in sepsis-induced lung injury is not clear. This study investigated the role and molecular mechanism of a novel circRNA in sepsis-induced lung injury and explored its prognostic value in patients with sepsis. In this study, aberrant circRNA expression profiling in lung tissues from mice with sepsis-induced lung injury was analyzed using high-throughput sequencing. circRNA-Cacna1d was verified by qRT-PCR, and its biological function in sepsis-induced lung injury was validated and . The interactions among circRNA-Cacna1d, microRNAs (miRNAs), and their downstream genes were verified. Furthermore, the clinical value of circRNA-Cacna1d in peripheral blood from patients with sepsis was also evaluated. We found that circRNA-Cacna1d expression was significantly increased in lung tissues of mice with sepsis and in microvascular endothelial cells after LPS challenge. circRNA-Cacna1d knockdown alleviated inflammatory response and ameliorated the permeability of vascular endothelium, thereby mitigating sepsis-induced lung injury and significantly improving the survival rate of mice with sepsis. Mechanistically, circRNA-Cacna1d directly interacted with miRNA-185-5p and functioned as a miRNA sponge to regulate the RhoA/ROCK1 signaling pathway. The expression level of circRNA-Cacna1d in patients with early sepsis was significantly higher than that in the healthy control subjects. Higher levels of circRNA-Cacna1d in patients with sepsis were associated with increased disease severity and poorer outcomes. In conclusions, circRNA-Cacna1d may play a role in sepsis-induced lung injury by regulating the RhoA/ROCK1 axis by acting as a miRNA-185-5p sponge. circRNA-Cacna1d is a potential therapeutic target for sepsis-induced lung injury and a prognostic biomarker in sepsis.
环状RNA（circRNAs）在脓毒症诱导的肺损伤中的作用尚不清楚。本研究调查了一种新型circRNA在脓毒症诱导的肺损伤中的作用和分子机制，并探讨了其在脓毒症患者中的预后价值。在本研究中，使用高通量测序分析了脓毒症诱导的肺损伤小鼠肺组织中异常的circRNA表达谱。通过qRT-PCR验证了circRNA-Cacna1d，并验证了其在脓毒症诱导的肺损伤中的生物学功能。验证了circRNA-Cacna1d、微小RNA（miRNAs）及其下游基因之间的相互作用。此外，还评估了circRNA-Cacna1d在脓毒症患者外周血中的临床价值。我们发现，脓毒症小鼠肺组织和LPS刺激后的微血管内皮细胞中circRNA-Cacna1d表达显著增加。敲低circRNA-Cacna1d可减轻炎症反应，改善血管内皮通透性，从而减轻脓毒症诱导的肺损伤，并显著提高脓毒症小鼠的存活率。机制上，circRNA-Cacna1d直接与miRNA-185-5p相互作用，并作为miRNA海绵发挥作用，调节RhoA/ROCK1信号通路。早期脓毒症患者中circRNA-Cacna1d的表达水平显著高于健康对照受试者。脓毒症患者中较高水平的circRNA-Cacna1d与疾病严重程度增加和预后较差相关。总之，circRNA-Cacna1d可能通过作为miRNA-185-5p海绵调节RhoA/ROCK1轴在脓毒症诱导的肺损伤中发挥作用。circRNA-Cacna1d是脓毒症诱导的肺损伤的潜在治疗靶点和脓毒症的预后生物标志物。
