Department of Neonatology, Kunming Children's Hospital, Kunming, Yunnan, China.
J Mol Histol. 2024 Nov 29;56(1):7. doi: 10.1007/s10735-024-10312-3.
Acute respiratory distress syndrome (ARDS) is a life-threatening condition associated with the inflammatory activation of alveolar macrophages. Here, we examined the role of circVAPA in regulating inflammasome activation and macrophage inflammatory polarization in an ARDS model.
circVAPA expression levels were analyzed in macrophages isolated from healthy controls and patients with ARDS. In vitro cell models of mouse alveolar macrophages and an in vivo mouse ARDS model were established through Lipopolysaccharide (LPS) stimulation. The effects of circVAPA knockdown on macrophage inflammatory polarization, inflammasome activation, and pulmonary tissue damage were investigated in both cell and animal models. The interaction between circVAPA and downstream factors was verified through a luciferase reporter assay and by silencing circVAPA.
circVAPA upregulation in alveolar macrophages was associated with the inflammation in ARDS patients. circVAPA was also upregulated in LPS-stimulated mouse alveolar macrophages (MH-S cells). Additionally, circVAPA knockdown attenuated the inflammatory activation of MH-S cells and reduced the expression of pyroptosis-related proteins. circVAPA silencing also mitigated the inflammatory effects of LPS-stimulated MH-S cells on lung epithelial cells (MLE-12), and alleviated the inflammatory damage in the pulmonary tissue of ARDS mouse model. We further showed that miR-212-3p/Sirt1 axis mediated the functional role of circVAPA in the inflammatory polarization of MH-S cells.
Our data suggest that circVAPA promotes inflammasome activity and macrophage inflammation by modulating miR-212-3p/Sirt1 axis in ARDS. Targeting circVAPA may be employed to suppress the inflammatory activation of alveolar macrophages in ARDS.
急性呼吸窘迫综合征（ARDS）是一种危及生命的疾病，与肺泡巨噬细胞的炎症激活有关。在这里，我们研究了 circVAPA 在调节 ARDS 模型中炎症小体激活和巨噬细胞炎症极化中的作用。
分析了来自健康对照者和 ARDS 患者的巨噬细胞中 circVAPA 的表达水平。通过脂多糖（LPS）刺激建立了小鼠肺泡巨噬细胞体外细胞模型和体内 ARDS 小鼠模型。在细胞和动物模型中，研究了 circVAPA 敲低对巨噬细胞炎症极化、炎症小体激活和肺组织损伤的影响。通过荧光素酶报告测定和沉默 circVAPA 验证了 circVAPA 与下游因子之间的相互作用。
肺泡巨噬细胞中 circVAPA 的上调与 ARDS 患者的炎症有关。LPS 刺激的小鼠肺泡巨噬细胞（MH-S 细胞）中也上调了 circVAPA。此外，circVAPA 敲低减弱了 MH-S 细胞的炎症激活，并降低了细胞焦亡相关蛋白的表达。circVAPA 沉默也减轻了 LPS 刺激的 MH-S 细胞对肺上皮细胞（MLE-12）的炎症作用，并减轻了 ARDS 小鼠模型中肺组织的炎症损伤。我们进一步表明，miR-212-3p/Sirt1 轴介导了 circVAPA 在 MH-S 细胞炎症极化中的功能作用。
我们的数据表明，circVAPA 通过调节 miR-212-3p/Sirt1 轴促进炎症小体的活性和巨噬细胞炎症，在 ARDS 中发挥作用。靶向 circVAPA 可能被用于抑制 ARDS 中肺泡巨噬细胞的炎症激活。
