肺成纤维细胞活化是肺纤维化发生的核心环节，国内外研究多聚焦于抑制其增殖及胶原分泌，对促进其凋亡及相关机制研究较少。我们前期研究显示名医经验方虎芪饮中陈皮碱性提取物具有很好的抗肺纤维化作用，可上调肺组织PGE2、EP2、COX-2水平和诱导小鼠肺成纤维细胞凋亡，提示可能与细胞凋亡相关。为此，本项目创新性的提出调控肺成纤维细胞凋亡可能是陈皮碱性提取物抗肺纤维化新机制。因此，本项目利用肺纤维化体内外模型，首先明确陈皮碱性提取物抗肺纤维化作用与促进肺成纤维细胞凋亡的关系；然后分别利用Fas和COX-2基因敲除、基因转染技术，研究陈皮碱性提取物对肺成纤维细胞凋亡、Fas、PGE2和COX-2分子的影响，进一步阐明陈皮碱性提取物通过PGE2介导的Fas/FasL信号通路调控肺成纤维细胞凋亡的机制。本项目期待从新的视角阐明陈皮碱性提取物抗肺纤维化的作用机制，预期研究成果可望为药物治疗肺纤维化提供新策略。

Activation of fibroblast is the central event in pulmonary fibrosis. Reported studies have mainly been focused on inhibition of fibroblast proliferation and its collagen secretion. Apoptosis of activated fibroblast and the related molecular mechanism are rarely investigated. Our previous studies showed that the alkaline extract of pericarp of citrus reticulata prepared from Hu-Qi-Yin, a Chinese herbal empirical prescription formulated by a famous doctor, potently inhibited pulmonary fibrosis, and upregulated the levels of PGE2, EP2, COX-2 and induced the apoptosis of fibroblast prepared from mice. These results suggested that the anti-fibrotic effect of the extract might correlated with apoptosis. Therefore, we creatively suggest that the alkaline extract might induce apoptosis of fibroblast that would be the new mechanism of anti-pulmonary fibrosis of the extract. To validate the hypotheses, the current project firstly focuses on clarifying the correlation between the antifibrotic effects and apoptosis of pulmonary fibroblast of the extract using animal lung fibrosis model. Then, the project aims at investigation on the effects of the extract on apoptosis of lung fibroblast and expressions of Fas, PGE2 and COX-2 using the techniques of gene knockout, gene transfection. Furthermore, the project takes aim at clarifying the mechanism of the extract on regulation of fibroblast apoptosis via Fas/FasL signal pathways mediated by PGE2. The project may elucidate the anti-pulmonary fibrosis effect and mechanism of the alkaline extract from a novel perspective, and provide a new insight on developing antifibrotic agent for clinical application.