基于CX3CL1/CX3CR1轴研究人参皂苷Re抗肺纤维化的分子作用机制

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 (CX3CLl) is a key factor which lead to pulmonary fibrosis in inflammatory cell recruitment to the pulmonary vascular wall. It is reported that the development of pulmonary fibrosis is related to innflammatory chemokines such as CX3CL1/CX3CR1 biological axis. CX3CL1can activate several signal transduction pathways, such as NF-κB pathway and TGF-β1/smad, to regulate the function of fibroblasts and macrophages, and to promote fibrosis. CX3CL1/CXCR1 has become a new key target for the treatment of pulmonary fibrosis. Previous studies showed that ginsenosides Re (Re) has anti pulmonary fibrosis effect, and its mechanism is closely related to the regulation of CX3CL1/CXCR1 axis. In this project, CX3CL1gene was silenced /overexpressed in human embryonic lung fibroblasts, and the effect of Re on signal transduction pathway was observed. Then, the therapeutic effect of Re was observed in cx3cl1 knockout / overexpression mice. The aim of this project is to explore the role of Re in anti pulmonary fibrosis and its molecular mechanism, and to find a new drug target.

肺纤维化(PF)是呼吸系统难治性疾病，对人类健康危害极大。炎症趋化因子CX3CLl/CX3CRl轴与PF发生密切相关。CX3CLl与CX3CRl结合，通过G蛋白耦联，启动NF-κB与TGF-β/Smad等多种细胞信号转导通路，调节纤维细胞和巨噬细胞功能，发挥促纤维化活性。抑制CX3CL1或CX3CR1可减少巨噬细胞与成纤维细胞聚集，减轻PF的严重程度。故CX3CL1/CX3CR1轴已成为治疗PF新的关键靶标。本项目前期研究发现人参皂苷Re具有抗PF作用，其机制与调节CX3CL1/CX3CR1轴密切相关。本项目首先在人胚肺成纤维细胞中，沉默/过表达CX3CL1基因，观察Re的作用及对相关信号转导途径的影响；再在CX3CL1基因敲除/过表达小鼠中，观察Re的治疗作用，为探讨Re抗PF的分子机制，发现新的药物靶标奠定基础。

肺纤维化是呼吸系统难治性疾病，对人类健康危害极大。炎症趋化因子CX3CLl/CX3CRl轴与肺纤维化发生密切相关。CX3CLl与CX3CRl结合，通过G蛋白耦联，启动NF-κB与TGF-β/Smad等多种细胞信号转导通路，调节纤维细胞和巨噬细胞功能，发挥促纤维化活性。抑制CX3CL1或CX3CR1可减少巨噬细胞与成纤维细胞聚集，减轻肺纤维化的严重程度。故CX3CL1/CX3CR1轴已成为治疗肺纤维化新的关键靶标。本项目前期研究发现人参皂苷Re具有抗肺纤维化作用，其机制与调节CX3CL1/CX3CR1轴密切相关。本项目首先明确在Re具有抗肺纤维化作用前提下，利用CX3CL1基因敲除/过表达小鼠，探讨Re抗肺纤维化的分子机制与CX3CL1/CX3CR1轴的关系；再在人胚肺成纤维细胞中，沉默/过表达CX3CL1基因，探讨Re的作用与相关信号转导途径的关系。结果发现人参皂苷Re抗肺纤维化作用与CX3CL1/CX3CR1有关，CX3CL1基因表达降低会抑制人参皂苷Re抗肺纤维化的作用；同时，Re抗肺纤维化作用涉及对ERK1/2信号通路、基质金属蛋白酶系统及Nrf2/Keap-1/ARE的调节。CX3CL1/CX3CR1 轴可激活多条信号转导通路相，参与急性、慢性炎症过程，介导细胞增殖，粘附，促进细胞分泌炎症因子、促进细胞基质沉积，上皮间质转化等调控肺纤维化进展。因此，CX3CL1/CX3CR1轴可能成为肺纤维化的潜在治疗靶点，为肺纤维化的治疗提供了新的研究方向。