Chen Yonghu, Wu Xilin, Jiang Zhe, Li Xuezheng
College of Pharmacy, Yanbian University Hospital, Yanbian University, Yanji, China.
Front Pharmacol. 2025 Jan 7;15:1461931. doi: 10.3389/fphar.2024.1461931. eCollection 2024.
Acute lung injury (ALI) is a severe condition characterized by inflammation, tissue damage, and persistent activation of the cyclic GMP-AMP (cGAS)-stimulator of interferon genes (STING) pathway, which exacerbates the production of pro-inflammatory mediators and promotes the progression of ALI. Specific inhibition of this pathway has been shown to alleviate ALI symptoms. Kaempferol-3---L-(4″--p-coumaroyl)-rhamnoside (KAE), an active compound found in the flowers of Kitagawa, exhibits anti-inflammatory and antioxidant properties. This study aimed to investigate the molecular mechanisms through which KAE regulates the cGAS-STING pathway in the context of ALI.
ALI was induced using LPS. Lung damage and anti-inflammatory/antioxidant effects were assessed by H&E staining, lung edema index, and SOD, MDA, and ELISA assays. NO release and mitochondrial membrane potential (MMP) were measured by JC-1 and Griess methods. The impact of KAE on the cGAS-STING pathway and PANoptosis was analyzed using flow cytometry, Western blot, and immunofluorescence.
KAE significantly alleviated lipopolysaccharide-induced pulmonary injury by reducing inflammatory cell infiltration, alleviating pulmonary edema, enhancing antioxidant capacity, and decreasing levels of inflammatory cytokines in mouse lung tissues. In both and analyses, KAE downregulated the expression of key components of the cGAS-STING pathway, including cGAS, STING, p-TBK1, and nuclear factor-κB. KAE also reduced the assembly and activation of the PANoptosome, thereby attenuating apoptosis, necroptosis, and pyroptosis. Additionally, KAE inhibited cGAS activation by restoring the MMP, which reduced the release of cytosolic DNA.
KAE improve ALI by inhibiting the release of cytosolic DNA and suppressing cGAS-STING pathway activation, thereby protecting cells from PANoptosis. Our findings provide valuable insights for the development and application of novel therapeutic strategies for ALI.
急性肺损伤（ALI）是一种严重病症，其特征为炎症、组织损伤以及环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）通路的持续激活，这会加剧促炎介质的产生并促进ALI的进展。已证明特异性抑制该通路可缓解ALI症状。山奈酚-3-O-L-(4″-O-对香豆酰基)-鼠李糖苷（KAE）是在北川花中发现的一种活性化合物，具有抗炎和抗氧化特性。本研究旨在探讨KAE在ALI背景下调节cGAS-STING通路的分子机制。
使用脂多糖诱导ALI。通过苏木精-伊红（H&E）染色、肺水肿指数以及超氧化物歧化酶（SOD）、丙二醛（MDA）和酶联免疫吸附测定（ELISA）分析评估肺损伤和抗炎/抗氧化作用。采用JC-1和格里斯方法测量一氧化氮（NO）释放和线粒体膜电位（MMP）。使用流式细胞术、蛋白质免疫印迹法和免疫荧光分析KAE对cGAS-STING通路和PAN凋亡的影响。
KAE通过减少炎症细胞浸润、减轻肺水肿、增强抗氧化能力以及降低小鼠肺组织中炎性细胞因子水平，显著减轻脂多糖诱导的肺损伤。在流式细胞术和蛋白质免疫印迹分析中，KAE均下调了cGAS-STING通路关键成分的表达，包括cGAS、STING、磷酸化TANK结合激酶1（p-TBK1）和核因子-κB。KAE还减少了PAN凋亡小体的组装和激活，从而减轻细胞凋亡、坏死性凋亡和炎性小体介导的细胞焦亡。此外，KAE通过恢复MMP抑制cGAS激活，这减少了胞质DNA的释放。
KAE通过抑制胞质DNA释放并抑制cGAS-STING通路激活来改善ALI，从而保护细胞免受PAN凋亡。我们的研究结果为ALI新型治疗策略的开发和应用提供了有价值的见解。
