Department of Emergency, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.
Trauma Center/Department of Emergency Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.
Int J Exp Pathol. 2024 Feb;105(1):21-32. doi: 10.1111/iep.12497. Epub 2023 Dec 6.
Sepsis-induced acute lung injury (ALI) is an inflammatory condition involving the pyroptosis of macrophages. This study investigated the role of circular RNA hsa_circ_0006990 (circVAPA) in regulating macrophage pyroptosis in ALI and the underlying mechanisms. The expression pattern of circVAPA was examined in the mouse model of ALI and in the LPS-treated RAW264.7 macrophage cell line. Lung tissue damage was evaluated by haematoxylin and eosin staining, immunohistochemistry and a myeloperoxidase activity assay. The molecular mechanisms were investigated by luciferase reporter assay, western blot, RT-qPCR and ELISA. circVAPA was down-regulated in the lung tissues of ALI mice and LPS-induced RAW264.7 cells. circVAPA over-expression alleviated lung tissue injury and dampened LPS-induced pyroptosis and Th17-associated inflammatory responses. miR-212-3p was identified as a target of circVAPA, and miR-212-3p negatively regulated the expression of Sirt1. Sirt1 knockdown largely abolished the effect of circVAPA over-expression on pyroptosis. CircVAPA/miR-212-3p/Sirt1 axis also regulates Nrf2 and NLRP3 expression upon LPS challenge. By targeting miR-212-3p, circVAPA over-expression negatively regulates the expression of Sirt1 and pyroptosis-related factors (Nrf2 and NLRP3), which alleviates the inflammatory damages in sepsis-induced ALI.
脓毒症诱导的急性肺损伤 (ALI) 是一种炎症状态，涉及巨噬细胞的细胞焦亡。本研究探讨了环状 RNA hsa_circ_0006990 (circVAPA) 在调节 ALI 中巨噬细胞细胞焦亡中的作用及其潜在机制。检测了 ALI 小鼠模型和 LPS 处理的 RAW264.7 巨噬细胞系中 circVAPA 的表达模式。通过苏木精和伊红染色、免疫组织化学和髓过氧化物酶活性测定评估肺组织损伤。通过荧光素酶报告基因测定、western blot、RT-qPCR 和 ELISA 研究了分子机制。在 ALI 小鼠和 LPS 诱导的 RAW264.7 细胞中，circVAPA 的表达下调。circVAPA 的过表达减轻了肺组织损伤，并抑制了 LPS 诱导的细胞焦亡和 Th17 相关炎症反应。miR-212-3p 被鉴定为 circVAPA 的靶标，miR-212-3p 负调控 Sirt1 的表达。Sirt1 敲低在很大程度上消除了 circVAPA 过表达对细胞焦亡的影响。circVAPA/miR-212-3p/Sirt1 轴也调节 LPS 刺激下 Nrf2 和 NLRP3 的表达。通过靶向 miR-212-3p，circVAPA 的过表达负调控 Sirt1 和细胞焦亡相关因子 (Nrf2 和 NLRP3) 的表达，减轻脓毒症诱导的 ALI 中的炎症损伤。
