瑞香素通过上调 CD38 抑制 MAPK/NF-κB/NLRP3 通路缓解脂多糖诱导的肺损伤。
Up-regulated CD38 by daphnetin alleviates lipopolysaccharide-induced lung injury via inhibiting MAPK/NF-κB/NLRP3 pathway.
机构信息
Department of Clinical Laboratory, Jiangxi Provincial People's Hospital and The First Affiliated Hospital of Nanchang Medical College, Nanchang, China.
Department of Medical Microbiology and Immunology, School of Basic Medical Sciences, Nanchang University, Nanchang, China.
出版信息
Cell Commun Signal. 2023 Mar 30;21(1):66. doi: 10.1186/s12964-023-01041-3.
BACKGROUND
Sepsis is a life-threatening organ dysfunction syndrome resulted from severe infection with high morbidity and mortality. Cluster of differentiation 38 (CD38) is a multifunctional type II transmembrane glycoprotein widely expressed on the surface of various immunocytes membranes that mediates host immune response to infection and plays an important role in many inflammatory diseases. Daphnetin (Daph), isolated from the daphne genus plant, is a natural coumarin derivative that possesses anti-inflammatory and anti-apoptotic effects. The current study aimed to investigate the role and mechanism of Daph in alleviating lipopolysaccharide (LPS)-induced septic lung injury, and to explore whether the protective effect of Daph in mice and cell models was related to CD38.
METHODS
Firstly, network pharmacology analysis of Daph was performed. Secondly, LPS-induced septic lung injury in mice were treated with Daph or vehicle control respectively and then assessed for survival, pulmonary inflammation and pathological changes. Lastly, Mouse lung epithelial cells (MLE-12 cells) were transfected with CD38 shRNA plasmid or CD38 overexpressed plasmid, followed by LPS and Daph treatment. Cells were assessed for viability and transfection efficiency, inflammatory and signaling.
RESULTS
Our results indicated that Daph treatment improved survival rate and alleviated pulmonary pathological damage of the sepsis mice, as well as reduced the excessive release of pro-inflammatory cytokines IL-1β, IL-18, IL-6, iNOS and chemokines MCP-1 regulated by MAPK/NF-κB pathway in pulmonary injury. Daph treatment decreased Caspase-3 and Bax, increased Bcl-2, inhibited nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis in lung tissues of septic lung injury. Also, Daph treatment reduced the level of excessive inflammatory mediators, inhibited apoptosis and pyroptosis in MLE-12 cells. It is noteworthy that the protective effect of Daph on MLE-12 cells damage and death was assisted by the enhanced expression of CD38.
CONCLUSIONS
Our results demonstrated that Daph offered a beneficial therapeutic effect for septic lung injury via the up-regulation of CD38 and inhibition of MAPK/NF-κB/NLRP3 pathway. Video Abstract.
背景
脓毒症是一种由严重感染引起的危及生命的器官功能障碍综合征，具有高发病率和死亡率。分化簇 38（CD38）是一种广泛表达于各种免疫细胞表面的多功能 II 型跨膜糖蛋白，它介导宿主对感染的免疫反应，在许多炎症性疾病中发挥重要作用。瑞香素（Daph）是从瑞香科植物中分离得到的一种天然香豆素衍生物，具有抗炎和抗凋亡作用。本研究旨在探讨 Daph 缓解脂多糖（LPS）诱导的脓毒症肺损伤的作用及其机制，并探讨 Daph 在小鼠和细胞模型中的保护作用是否与 CD38 有关。
方法
首先，对 Daph 进行网络药理学分析。其次，用 Daph 或载体对照分别处理 LPS 诱导的脓毒症肺损伤小鼠，然后评估其存活率、肺炎症和病理变化。最后，用 CD38 shRNA 质粒或 CD38 过表达质粒转染小鼠肺上皮细胞（MLE-12 细胞），然后用 LPS 和 Daph 处理。评估细胞活力和转染效率、炎症和信号。
结果
结果表明，Daph 治疗可提高脓毒症小鼠的存活率，减轻肺组织病理损伤，降低 MAPK/NF-κB 通路调节的过度炎症因子 IL-1β、IL-18、IL-6、iNOS 和趋化因子 MCP-1 的释放。Daph 治疗可降低脓毒症肺损伤肺组织 Caspase-3 和 Bax，增加 Bcl-2，抑制核苷酸结合域（NOD）样受体蛋白 3（NLRP3）炎症小体介导的细胞焦亡。此外，Daph 治疗可降低 MLE-12 细胞中过度炎症介质的水平，抑制细胞凋亡和焦亡。值得注意的是，Daph 增强 CD38 的表达有助于其对 MLE-12 细胞损伤和死亡的保护作用。
结论
本研究表明，Daph 通过上调 CD38 和抑制 MAPK/NF-κB/NLRP3 通路对脓毒症肺损伤具有有益的治疗作用。视频摘要。
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