Zhang Sijia, Hu Dongsheng, Zhuo Yuzhen, Cui Lingzhi, Li Dihua, Zhang Lanqiu, Yang Lei, Wang Ximo
Graduate School, Tianjin Medical University, Tianjin, China.
Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital, Tianjin, China.
Naunyn Schmiedebergs Arch Pharmacol. 2023 Nov;396(11):3269-3283. doi: 10.1007/s00210-023-02534-1. Epub 2023 May 27.
The primary objectives of this research were to investigate the protective effects of liriodendrin against IgG immune complex (IgG-IC)-induced acute lung injury (ALI) and to elucidate the underlying mechanisms. This study employed a mouse and cell model of IgG-IC-induced acute lung injury. Lung tissue was stained with hematoxylin-eosin to observe pathological alterations and arterial blood gas analysis was tested. Inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α), were measured using ELISA. The mRNA expression of inflammatory cytokines was assessed via RT-qPCR. Molecular docking and enrichment analysis were combined to identify the most potential signaling pathways modulated by liriodendrin, which were then verified using western blot analysis in IgG-IC-induced ALI models. We identified 253 shared targets between liriodendrin and IgG-IC-induced acute lung injury from the database. Through network pharmacology, enrichment analysis, and molecular docking, SRC was determined to be the most closely associated target of liriodendrin in IgG-IC-induced ALI. Pretreatment with liriodendrin notably reduced the increased cytokine secretion of IL-1β, IL-6, and TNF-α. Histopathological analysis of lung tissue demonstrated a protective effect of liriodendrin on IgG-IC-induced acute lung injury in mice. Arterial blood gas analysis showed liriodendrin ameliorated acidosis and hypoxemia efficiently. Further studies revealed that liriodendrin pretreatment substantially attenuated the elevated phosphorylation levels of SRC's downstream components (JNK, P38, and STAT3), suggesting that liriodendrin may protect against IgG-IC-induced ALI via the SRC/STAT3/MAPK pathway. Our findings indicate that liriodendrin protects against IgG-IC-induced acute lung injury by inhibiting the SRC/STAT3/MAPK signaling pathway, suggesting that liriodendrin may serve as a potential treatment for acute lung injury caused by IgG-IC.
本研究的主要目的是探讨鹅掌楸苷对IgG免疫复合物（IgG-IC）诱导的急性肺损伤（ALI）的保护作用，并阐明其潜在机制。本研究采用了IgG-IC诱导的急性肺损伤小鼠和细胞模型。用苏木精-伊红对肺组织进行染色以观察病理改变，并进行动脉血气分析。采用酶联免疫吸附测定法（ELISA）检测包括白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）在内的炎性细胞因子。通过逆转录定量聚合酶链反应（RT-qPCR）评估炎性细胞因子的mRNA表达。结合分子对接和富集分析来确定鹅掌楸苷调节的最具潜力的信号通路，然后在IgG-IC诱导的ALI模型中使用蛋白质免疫印迹分析进行验证。我们从数据库中确定了鹅掌楸苷和IgG-IC诱导的急性肺损伤之间的253个共同靶点。通过网络药理学、富集分析和分子对接，确定SRC是鹅掌楸苷在IgG-IC诱导的ALI中最密切相关的靶点。用鹅掌楸苷预处理可显著降低IL-1β、IL-6和TNF-α细胞因子分泌的增加。肺组织的组织病理学分析表明鹅掌楸苷对IgG-IC诱导的小鼠急性肺损伤具有保护作用。动脉血气分析显示鹅掌楸苷能有效改善酸中毒和低氧血症。进一步研究表明，鹅掌楸苷预处理可显著降低SRC下游成分（JNK、P38和STAT3）的磷酸化水平升高，提示鹅掌楸苷可能通过SRC/STAT3/丝裂原活化蛋白激酶（MAPK）途径预防IgG-IC诱导的ALI。我们的研究结果表明，鹅掌楸苷通过抑制SRC/STAT3/MAPK信号通路来预防IgG-IC诱导的急性肺损伤，提示鹅掌楸苷可能作为IgG-IC所致急性肺损伤的一种潜在治疗药物。
