基于TLRs/MyD88信号和hUAT、hURAT1探讨苗药痛风停方抗痛风的机制研究

Hyperuricemia is the most important biochemical basis and the most directest risk factor of gout. Human urate transporter (hUAT) and Human urate-anion transporter 1(hURAT1), the key ion channels to maintain blood uric acid level, are important targets for urate-1owering agents. Toll like receptors/myeloid differentiation factor 88 (TLRs/MyD88) is the hub of cascade reaction pathway, which causing the inflammation of gout. The activation of these pathways regulates the expression of inflammatory genes, promotes the occurrence of joint inflammation. So that the inhibiton of the abnormal activation of TLRs/MyD88 pathways and regulation of the expression of hUAT and hURAT1 genes may become the new target treatment of gout. Based on the difficulties and bottlenecks of gout treatment, we combined the TCM "heat and blood stasis" theory and the Miao medicine "Pathogenic Fire and Toxin" theory, concoted the "gout arrest" which mainly composed of Guizhou Miao medicine.Based on previous clinical and experimental research, and in order to lay the foundation of the study about promoting the TCM targeting treatment of gout, we will establish gouty arthritis and hyperuricemia animal models, and research the influence of the "gout arrest" on the expression of hUAT/hUAT1 of renal tubular epithelial cells of hyperuricemia models and the TLRs/MyD88 signaling pathway of gouty arthritis models.

高尿酸血症是痛风发作最重要的生化基础和最直接的危险因素，人尿酸盐转运子(hUAT)和尿酸盐转运蛋白1(hURAT1)是维持血尿酸水平的关键离子通道，是降尿酸药物的重要靶点。Toll样受体/髓样分化因子88（TLRs/MyD88）信号是引发痛风炎症级联反应通路的枢纽，其信号途径的激活调节炎性基因的表达，促进关节炎症的发生。因此抑制TLRs/MyD88信号途径的非正常激活及调控hUAT和hURAT1基因的表达可能成为痛风治疗的新靶点。基于痛风治疗的难点和瓶颈，课题组将痛风发病的中医“热毒血瘀”理论与苗医“火毒”理论相结合，以贵州苗药为主组成痛风停方，在前期临床和实验研究的基础上，通过建立痛风性关节炎和高尿酸血症动物模型，探讨苗药痛风停方对高尿酸血症模型肾小管上皮细胞hUAT、hURAT1表达和痛风性关节炎模型TLRs/MyD88信号通路的影响，为推动民族药靶向治疗痛风的研究奠定基础。

高尿酸血症是痛风发作最重要的生化基础和最直接的危险因素，人尿酸盐转运子(hUAT)和尿酸盐转运蛋白1(hURAT1)是维持血尿酸水平的关键离子通道，是降尿酸药物的重要靶点。Toll样受体/髓样分化因子88（TLRs/MyD88）信号是引发痛风炎症级联反应通路的枢纽，其信号途径的激活调节炎性基因的表达，促进关节炎症的发生。因此抑制TLRs/MyD88信号途径的非正常激活及调控hUAT和hURAT1基因的表达可能成为痛风治疗的新靶点。基于痛风治疗的难点和瓶颈，课题组将痛风发病的中医“热毒血瘀”理论与苗医“火毒”理论相结合，以贵州苗药为主组成痛风停方，在前期临床和实验研究的基础上，通过建立痛风性关节炎和高尿酸血症动物模型，证实了苗药痛风停汤能通过下调Toll样受体和MyD88信号通路的传导，抑制下游炎症因子IL-1、IL-8、COX-2的释放；同时苗药痛风停汤可以有效降低急性痛风性关节炎模型大鼠血清sTREM-1的表达及关节滑膜TREM-1、JAK2、p-JAK2、STAT3、p-STAT3表达；苗药痛风停汤剂可显著提高HK-2细胞内hOAT1、hUAT、hOAT3mRNA的表达，降低huRAT1mRNA表达，抑制Caspase-3蛋白活性，提高HK-2细胞活性；以上研究成果为推动民族药靶向治疗痛风的研究奠定了基础。