基于高尿酸与高脂微环境下的NALP3炎性小体活化探讨大麻药抗痛风作用机制研究

It is traditional known that although the most important risk factor for gout development is hyperuricemia, only one-tenth of hyperuricemic patients develop gout. Meanwhile, not all patients with gout are found to have hyperuricemia. These findings may reveal the potential possibility that factors other than hyperuricemia initiate or precipitate gout. Researches reported that some pathological products of hyperlipidemia could activate the NALP3 inflammasome in coordination with urate crystals, and then triggered the development of gout. However, the special reasons are not clear yet. Based on these researches, this study is carried out to investigate the anti-gouty effects of Dolichos falcatus Klein by aiming at the NALP3 inflammasome and the microenvironment of hyperuricemia and hyperlipidemia. Our previous researches indicated that Dolichos falcatus Klein had significant anti-gouty effect. Regulating the lipid metabolism and the inflammasome activation might be the possible mechanisms. Therefore, based on the previous studies, the NALP3 inflammasome activation and the anti-gouty effect of Dolichos falcatus Klein under the microenvironment of hyperuricemia and hyperlipidemia are investigated with in vitro inflammation models by pplasmids transfection , ShRNA and other techniques. Furthermore, the anti-gouty effect of Dolichos falcatus Klein are also studied from the lipid regulation, anti-hyperuricemia, anti-inflammation and other points with the methods of RT-PCR and western blotting analyses in vivo. These findings will provide the new visual fields and evidences on the prevention of gout.

传统认为痛风是因尿酸过高所致的疾病，但临床上只有1/10的高尿酸患者会发展成痛风，且不是所有痛风患者都具有高尿酸血症，这表明痛风的发生发展还存在其它诱因。据报道高脂血症的某些病理产物能协同尿酸盐结晶诱导NALP3炎性小体的活化，从而触发痛风，但此间缘由尚未明了。本课题针对这些现象，引入在痛风发生发展过程中发挥关键作用的NALP3炎性小体及其高尿酸与高脂微环境作为研究对象，进行大麻药干预研究。前期研究显示大麻药具有显著的抗痛风作用，初步表明其通过调控脂质代谢与炎性小体活化而起效。故本课题拟在前期研究基础上，建立体外炎症模型，应用质粒转染与ShRNA等技术，探讨高脂与高尿酸微环境下，病理产物活化NALP3炎性小体的作用机制；并进一步建立多种相关动物模型，运用RT-PCR与WB等方法，从调脂、降尿酸及抗炎等角度，综合诠释大麻药抗痛风作用机制，以期为痛风的发病机制研究与防治提供新思路。

传统认为痛风是因尿酸过高所致的疾病，但临床上只有1/10的高尿酸患者会发展成痛风，且不是所有痛风患者都具有高尿酸血症，这表明痛风的发生发展还存在其它诱因。本课题针对这一现象，引入在痛风中发挥关键作用的NALP3炎性小体及其高尿酸与高脂微环境作为研究对象，进行大麻药干预研究。通过3年的研究，我们基本弄清楚了高脂血症在高尿酸患者痛风发作中的重要作用，即高脂血症的一些代谢产物（如LDL，oxLDL）是TLRs-NF-KB通路的激活剂，其能促进高尿酸血症的析出产物尿酸盐结晶，诱导NLRP3- IL-1β通路，共凑痛风发作。因此从高脂血症这一角度，直接回答了临床上只有1/10的高尿酸患者会发展成痛风的背后分子事件。同时也建议在临床上，对于伴有高脂血症的高尿酸患者除应当开展降尿酸治疗，还应该积极开展降脂治疗，方能显著的预防痛风的发作。傣药大麻药及其有效成分能显著改善高脂和高尿酸血症，其通过抑制TLRs-NF-KB与NLRP3-IL-1β双通路的活化起到抗痛风的机制。这些研究为痛风的发病机制研究与防治提供了新思路。本课题共计发表论文6篇，其中SCI论文4篇，获得授权专利4项。