化学衍生结合液质联用技术解析SLE性激素异常表达谱及解毒祛瘀滋肾方的干预机制

SLE (systemic lupus erythematosus, SLE) occurs mostly in women of childbearing age, and abnormal sex hormone is considered to be one of the important factors in the pathogenesis of SLE. However, previous studies only concentrated on several common sex hormones, such as estradiol, testosterone, progesterone,etc, and didn’t pay attention to other metabolites within the hormone metabolism network. Recently, there are some western drugs for SLE therapy through regulating sex hormones, but long-term use will cause massive side effects. Clinical trials and experimental studies of our research group has found that Jieduquyuzishen prescription(JP) in the treatment of SLE could alleviate disease, reduce disease activity, regulate the immune system, and improve the endocrine disorder. Thus we assume that JP may adjust the abnormal metabolism of sex hormones to restore the body's immune function, which helps to alleviate the disease of SLE patients. To test the hypothesis, a highly sensitive detection method for steroid hormones based on chemical derivatization and liquid chromatography - mass spectrometry (LC-MS) will be developed and applied to capture the specific sex hormone patters among serum from SLE patients and healthy volunteers, and further to explain the relationship between sex hormones and the SLE; then, the intervention effect on sex hormone metabolism and related immune indexes of JP will be studied using MRL/lpr mice to explore possible mechanism of traditional Chinese medicine in the treatment of SLE. The research will provide new ideas for prevention and treatment of autoimmune diseases such as SLE.

系统性红斑狼疮(SLE）高发于育龄期女性，性激素异常被认为是其发病的重要因素之一，但是目前相关研究仅限于几种常见性激素，忽略了性激素代谢网络中的其他分子。近年来有一些针对性激素环节进行治疗的西药，但长期服用副作用极大。申请人所在课题组前期临床和实验研究发现解毒袪瘀滋肾方治疗SLE能缓解病情，降低疾病活动度，调节免疫系统，并且对内分泌紊乱有改善作用，因而我们推断该方可能通过调节异常的性激素代谢来修复机体免疫功能从而发挥疗效。结合前期研究基础，本项目拟利用化学衍生化和液相色谱-质谱联用技术开展SLE患者体内性激素的高灵敏分析，获取SLE相关的激素异常表达谱，明确性激素与SLE发生发展的相关性；进一步通过MRL/lpr狼疮鼠考察解毒祛瘀滋肾方对性激素代谢的干预作用，结合免疫相关指标，探讨中医药治疗SLE的可能机制。本课题的顺利开展可以为SLE等自身免疫性疾病的防治提供新思路。

系统性红斑狼疮（Systemic lupus erythematosus, SLE）是一种典型的自身免疫性疾病，好发于育龄期女性。性激素代谢异常被认为是其发病的重要因素之一，但是目前相关研究仅限于几种常见性激素，有必要开展更为全面、系统的性激素代谢谱的研究以确切地阐明性激素在SLE发生发展中的作用。.针对类固醇激素含量低且结构相似性高的难点，本研究首先完善了类固醇激素的代谢轮廓分析方法，可以实现对体液中75种激素及其代谢物的快速分析，主要包括雄性激素23种、雌性激素19种、孕激素14种、皮质激素15种以及甾醇4种。.与健康人群相比，SLE患者体内激素代谢谱出现了异常，雄性激素总量出现下调，雌性激素总量有上调趋势，14种激素分子在SLE患者与健康人群体内水平具有统计学差异，10种雄性激素（An、Etio、βαβ-diol、Epi-DHT、DHEA、Epi-An、A-diol、T、11β-OH-Etio、16α-OH-DHEA）和1种皮质激素（11-DeoxyF）显著减少，2种雌性激素（17α-E2和E3）和1种甾醇（Lan）显著增加，6种激素分子（An、Etio、Epi-An、A-diol、T和16α-OH-DHEA）与狼疮疾病活动度呈显著负相关。.课题组前期研究发现解毒祛瘀滋肾方治疗SLE具有较好的疗效，且副作用少，然而由于中药复方具有多成分、多靶点的作用特点，目前其治疗SLE的具体机制仍不明确。本研究发现经过解毒祛瘀滋肾方或泼尼松干预后，MRL/lpr小鼠病情缓解，尿蛋白显著减少，IL-6、IL-10和TNF-α等细胞因子水平出现降低，并且两种药物均可以一定程度上改善激素代谢，如上调了βαβ-dio、Epi-DHT和testosterone等雄性激素的水平，下调了17α-E2的水平等。对异常性激素代谢进行调节以修复机体免疫功能可能是解毒祛瘀滋肾方治疗SLE的重要机制之一。