背景:矽肺带来了巨大的临床挑战和经济负担,随着中医药(TCM)成为潜在的治疗途径。然而,中医药治疗矽肺的确切疗效和机制仍不确定,有待争论。
目的:本研究旨在阐明阳阴清肺汤(YYQFD)及其关键成分的治疗作用和机制,芍药苷,使用鼠模型在矽肺中。
方法:用YYQFD治疗矽肺小鼠,吡非尼酮(PFD),或者芍药苷.用二氧化硅刺激RAW264.7细胞和小鼠肺成纤维细胞(MLF),基质金属蛋白酶-12(MMP-12),或TGF-β1,然后用芍药苷治疗,PFD,或相关抑制剂。使用高效液相色谱法(HPLC)表征YYQFD成分。通过组织病理学检查评估肺纤维化严重程度,显微CT成像,肺功能,和蛋白质印迹分析。采用转录组测序和生物信息学分析来描绘矽肺中YYQFD调节的基因表达谱和靶基因。
结果:用YYQFD治疗可改善二氧化硅诱导的肺纤维化。转录组测序将MMP-12鉴定为YYQFD和PFD的潜在共同靶标。此外,由二氧化硅诱导的TLR4信号通路调节的MMP-12的潜在促炎作用,被揭露。芍药苷,YYQFD中最独特的化合物之一,通过直接结合作用减弱二氧化硅诱导的巨噬细胞MMP-12及其衍生的炎症因子的增加。值得注意的是,芍药苷治疗通过抑制MMP-12衍生的炎症因子和TGF-β1诱导的二氧化硅暴露小鼠肌成纤维细胞分化发挥抗纤维化作用。
结论:本研究强调芍药苷是YYQFD中最主要的生物活性化合物之一,强调其减轻由巨噬细胞衍生的MMP-12驱动的肺部炎症和减少体内和体外肺纤维化的能力。
BACKGROUND: Silicosis presents a significant clinical challenges and economic burdens, with Traditional Chinese Medicine (TCM) emerging as a potential therapeutic avenue. However, the precise effects and mechanisms of TCM in treating silicosis remain uncertain and subject to debate.
OBJECTIVE: The study aims to elucidate the therapeutic role and mechanisms of the Yang-Yin-Qing-Fei Decoction (YYQFD) and its key component, paeoniflorin, in silicosis using a murine model.
METHODS: Silicotic mice were treated with YYQFD, pirfenidone (PFD), or paeoniflorin. RAW264.7 cells and mouse lung fibroblasts (MLF) were stimulated with silica, matrix metalloproteinase-12 (MMP-12), or TGF-β1, followed by treatment with paeoniflorin, PFD, or relevant inhibitors. YYQFD constituents were characterized using High-Performance Liquid Chromatography (HPLC). Lung fibrosis severity was assessed via histopathological examination, micro-CT imaging, lung functions, and Western blot analysis. Transcriptome sequencing and bioinformatics analysis were employed to delineate the gene expression profile and target genes modulated by YYQFD in silicosis.
RESULTS: Treatment with YYQFD ameliorated silica-induced lung fibrosis. Transcriptome sequencing identified MMP-12 as a potential common target of YYQFD and PFD. Additionally, a potential pro-inflammatory role of MMP-12, regulated by silica-induced TLR4 signaling pathways, was revealed. Paeoniflorin, one of the most distinctive compounds in YYQFD, attenuated silica-induced MMP-12 increase and its derived inflammatory factors in macrophages through a direct binding effect. Notably, paeoniflorin treatment exerted anti-fibrotic effects by inhibiting MMP-12-derived inflammatory factors and TGF-β1-induced myofibroblast differentiation in silica-exposed mice.
CONCLUSIONS: This study underscores paeoniflorin as one of the most principal bioactive compounds in YYQFD, highlighting its capacity to attenuate lung inflammation driven by macrophage-derived MMP-12 and reduce lung fibrosis both in vivo and in vitro.