人参茎叶总皂苷及人参皂苷Rg1抗肺纤维化作用与机制

Pulmonary fibrosis (PF) is a ultimate ending for the multi-diffuse pulmonary interstitial diseases, and it is a intractable disease in respiratory system. It is indicated that the development of PF is related to multi-factors, such as oxygen radical injury, collagen metabolism disorder, abnormal matrix metalloproteinase and energy metabolism.Fractalkine (FKN) is a key factor which lead to pulmonary fibrosis in inflammatory cell recruitment to the pulmonary vascular wall. It is also shown that ginsenosides have effects of anti-oxidation, regulating matrix metalloproteinase expression, protecting acute pulmonary injury and inhibiting the elevated expression of TGF-β1 (a key factor for PF development) induced by antineoplastic drug. We conjecture that ginsenosides may have a anti-PF effect, and the results from our preliminay experiment also indicate this possibility.Unfortunately, it is not clear whether the protective mechanisms are involved in MMPs and TGF-β/Smad pathway and FKN. In this sudy, the possible anti-PF effects and the mechanisms of ginsenoside Rg1 and total ginsenosides from the stem and leaf of Panax ginseng will be observed in the bleomycin and monocrotaline -induced rat PF model, and mechanisms will be analyzed further from two aspects.The pulmonary index (pulmonary weight /body weight) will be calculated , and it will be taken the HE and masson stainings as well as the transmission electron microscope for histological observation; biochemical methods for anti-oxidation parameter tests; molecular biological methods for examining the mRNA or protein expressions of some cytokines (such as TGF-β1 ), and various funtional proteins involved in PF,such as α-SM actin、Smad proteins, and some metalloproteinases and their histological inhibiotors (MMP-9，TIMP-1). For study the relationship between ginsenoside Rg1 and total ginsenosides from the stem and leaf of Panax ginseng and FKN in Fkn knockout mice and the role of FKN in PF. These studies will help our understanding of pharmacological basis of ginsenoside Rg1 and total ginsenosides from the stem and leaf of Panax ginseng in protecting against PF, and search new drugs for PF treatment.

肺纤维化（PF)是呼吸系统难治性疾病。文献报道PF的发生发展与细胞因子网络（TGF-β1/Smad信号通路）、氧化损伤、基质金属蛋白酶(MMPs)等多种因素有关。趋化因子Fractalkine（FKN）是将募集炎症细胞，促进血管重塑进而导致肺纤维化的关键因素。已知人参皂苷类化合物具有抗氧化、调节基质金属蛋白酶表达、保护急性肺损伤和抑制药物所致转化生长因子-β1（TGF-β1，PF发展的关键因素）高表达等作用，因此，推测人参茎叶总皂苷(TG)及人参皂苷Rg1可能具有抗PF效应，预实验结果也提示这种可能性。我们认为TG与Rg1抗PF的机制可能涉及MMPs、TGF-β/Smad通路及FKN。本课题拟采用博来霉素及野百合碱（MCT）所致大鼠肺纤维化模型，进一步观察TG及Rg1抗PF作用，并利用FKN基因敲除小鼠探讨其作用机制。

肺纤维化是呼吸系统难治性疾病，其发生发展与细胞因子网络（TGF-β1/Smad信号通路）、氧化损伤、基质金属蛋白酶等多种因素有关。趋化因子Fractalkine（FKN）是将募集炎症细胞，促进血管重塑进而导致肺纤维化的关键因素。申请人前期研究结果表明，人参总皂苷能明显减轻注射野百合碱所致大鼠肺部小血管的损伤，显著降低野百合碱所升高的肺系数（肺重/ 体重），提示人参总皂苷有抑制肺动脉高压/肺纤维化的潜在可能性。本项目在前期研究工作基础上，通过建立博来霉素诱导的小鼠肺纤维化模型、野百合碱诱导的大鼠肺动脉高压/肺纤维化模型及CX3CL1基因敲除小鼠模型，结合运用病理形态学、生化检测技术及分子生物学检测技术等，从整体水平证实了人参总皂苷及人参皂苷Rg1抗肺纤维化的效应与机制，为其临床用于治疗肺纤维化及肺动脉高压提供基础药理学实验依据。