穿心莲内酯治疗肺纤维化的作用及分子机制研究

Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible and devastating interstitial lung disease characterized by alveolar structure destruction, interstitial inflammation, collagen deposition, lung tissue remodeling and aberrant re-epithelization, eventually leading to loss of lung function and respiratory failure. Although great efforts have been made, the detailed mechanism of IPF is still largely unknown and it is still a king of disease with unknown etiology and few treatment options, which seriously threats to human health and life. Therefore, it is imperative to investigate the mechanism of this disease and explore a novel therapy. Andrographolide was a bicyclic diterpenoid lactone isolated from the plant andrographis paniculata. Our previous study also demonstrated that andrographolide apparently ameliorated BLM-induced collagen deposition and improved lung function. Based on our previous research, we would adopt a rat model of BLM-induced pulmonary fibrosis and apply pharmacological and molecular biological techniques, combining with in vivo and in vitro experiments, to investigate the effect and the mechanisms of andrographolide on the epithelial injury, impaired epithelial-mesenchymal communication and fibroblasts activation. Successful completion of these studies will help improving the understanding of underlying this disease mechanism and yielding novel therapeutic method for the patients with chronic fibrotic lung disease.

特发性肺纤维化（IPF）是以进行性、不可逆性的肺泡结构破坏为特征，最终导致肺功能丧失和呼吸衰竭的间质性肺疾病，严重威胁人类健康和生命，但机制不详，缺乏有效治疗药物。因此，深入研究其发病机制，探索新的治疗药物具有重要的意义。穿心莲内酯是我国传统中药穿心莲的主要有效成分，我们近期初步的实验结果证明穿心莲内酯能够改善肺纤维化大鼠的肺功能，减轻博来霉素诱发的肺纤维化。本项目将在前期研究成果的基础上，拟用博来霉素诱导的肺纤维化疾病大鼠模型，结合体外细胞培养技术，应用药理学、分子生物学等实验手段，进一步研究穿心莲内酯是否通过抑制TGF-β1信号通路，进而抑制肺纤维化形成过程中的三个关键环节（上皮细胞损伤、成纤维细胞激活与转化和上皮细胞—成纤维细胞异常通讯）发挥保护作用。本研究将加深对IPF发病机制的新认识，并为临床治疗肺纤维化疾病提供新的治疗手段。

特发性肺纤维化（IPF）是以进行性、不可逆性的肺泡结构破坏为特征，最终导致肺功能 丧失和呼吸衰竭的间质性肺疾病，严重威胁人类健康和生命，但机制不详，缺乏有效治疗药物。因此，深入研究其发病机制，探索新的治疗药物具有重要的意义。穿心莲内酯是我国传统中 药穿心莲的主要有效成分。本项目利用博来霉素（BLM）诱导的肺纤维化疾病大鼠模型，结合体外细胞培养技术，应用药理学、分子生物学等实验手段，进一步研究穿心莲内酯是否通过抑制TGF-β1信号通路，进而抑制肺纤维化形成过程中的三个关键环节（上皮细胞损伤、成纤维细胞激活与转化和上皮细胞—成纤维细胞异常通讯）发挥保护作用。我们的研究发现穿心莲内酯（Andro）能够通过抑制TGF-β1介导的Smad2/3和Erk1/2信号通路，抑制肺成纤维细胞的增殖、转化和合成细胞外基质（ECM）成分，促进其凋亡。穿心莲内酯（Andro）能够通过抑制TGF-β1介导的Smad2/3和Erk1/2信号通路，抑制上皮间质转化（ECM），这与Sirt1/FOXO3介导的氧化应激的抑制密切相关。在BLM诱导的肺纤维化模型中，穿心莲内酯（Andro）能够显著抑制成纤维细胞的增殖和转化，以及抑制EMT的发生。此外，穿心莲内酯（Andro）能够抑制肺上皮细胞-成纤维细胞异常通讯，进而减轻BLM诱导的肺纤维化。我们的研究成果进一步系统阐明穿心莲内酯治疗肺纤维化的分子作用机制，为进一步开发治疗肺纤维化新型高效药物奠定研究基础，推动开发具有我国自主知识产权的肺纤维化新型药物，为传统中药临床转化提供了广阔的开发前景。