臺灣博碩士論文加值系統

紅斑性狼瘡為一種自體免疫疾病，特徵為病人血清中含有許多種自體抗體，進而經由免疫發炎機轉，導致程度不一的全身器官病變，其中最會影響到患者預後的器官便是腎臟。因為其高好發率及高致死率，狼瘡腎炎成為紅斑性狼瘡最主要的併發症之一，許多狼瘡腎炎患者發展成為慢性腎臟病，最後甚至因為腎衰竭和尿毒症而死亡，其中又以腎臟病理型態學分類為增生型腎炎之惡化型狼瘡腎炎的預後最差。目前對狼瘡腎炎的致病機轉雖然尚未明瞭，但全身性免疫調節異常、發炎反應及活性氧導致之氧化壓力，被認為在狼瘡腎炎的發生及惡化中扮演了重要的角色。臨床上應用於狼瘡腎炎的治療主要以類固醇或免疫抑制劑單獨或合併使用，然而這些藥物通常伴隨許多相當嚴重的副作用。傳統中草藥因為安全性高，一般民眾接受度高，因此，愈來愈多研究者致力於開發中草藥成為替代治療用藥或西藥之輔佐用藥。本論文分別評估具有抗發炎功效之中草藥複方DCB-SLE1和牛樟芝純化物antroquinonol對於加速惡化型狼瘡腎炎之療效，及長期給予具有抗氧化能力之綠茶沒食子酸酯化兒茶素（epigallocatechin-3-gallate, EGCG）對於減緩自發型狼瘡腎炎發生之效果評估。結果發現：1. DCB-SLE1能藉由抑制B細胞活化及降低自體抗體產生；抑制T細胞活化及增生；降低介白素(interleukin, IL)-6、IL-17及IL-18表現及阻斷細胞核內轉錄因子nuclear factor-kappa B之活化，而達到改善小鼠加速惡化型狼瘡腎炎之惡化。2. Antroquinonol則藉由抑制T細胞活化/增生；增加調節性T細胞數量及活性並降低IL-18表現；活化nuclear factor-erythroid-2-related factor 2之抗氧化訊息傳遞路徑，達到減緩小鼠加速惡化型狼瘡腎炎之惡化。3.長期給予EGCG不僅能有效降低小鼠體內活性氧含量，更進一步能夠抑制NLRP3發炎體活化及增加調節性T細胞功能，明顯降低全身性紅斑性狼瘡發展成為狼瘡腎炎。因此，DCB-SLE1、antroquinonol或EGCG具有很大的潛能在未來開發成為狼瘡腎炎的輔佐用藥。

Systemic lupus erythematosus (SLE) is an autoimmune disorder involving multiple organs injury due to autoantibody production and abnormal cell immunity. Lupus nephritis, one of the most severe complications of SLE, is associated with significant morbidity and mortality. The cumulative risks of end stage renal failure were particularly high in patients with severe lupus nephritis, the histopathology of which comprises distinct patterns of injury that were initially defined by the World Health Organization Classification of 1982 as category III, category IV, and categories Vc and Vd. Although the exact mechanisms for the development or the progression of lupus nephritis remain unclear, abnormal cellular and humoral autoimmunity, inflammation, and oxidative stress have been implicated. Current therapies for lupus nephritis are various combinations of corticosteroids with other cytotoxic agents or immunomodulators, but many of these have various side effects. Importantly, Chinese herbal medicines have long been considered as typically a mild remedy with little or no side effects, and endeavors on developing them to be used as complementary components or adjuvants to Western medicines have been increasingly made over the past years in pharmaceutical research and industry. This thesis study tested the hypothesis that DCB-SLE1, an extract of a mixture of Chinese medicinal herbs, and antroquinonol, a purified compound with a major effective component of Antrodia camphorata, might ameliorate accelerated severe lupus nephritis by modulating pathophysiological pathways of abnormal immunity, inflammation, and oxidative stress. Moreover, we also tested the hypothesis that epigallocatechin-3-gallate (EGCG), the major bioactive polyphenol presents in green tea with antioxidant and free radical scavenging activities, can prevent development of lupus nephritis by long-term administering it to New Zealand black/white (NZB/W) F1 lupus-prone mice. The results showed that: (1) DCB-SLE1 protected the kidney from autoimmune response-mediated acute and severe damage through systemic immune modulation and anti-inflammation pathways; (2) Antroquinonol administration significantly ameliorated the development of severe renal lesions via differentially regulating T cell function and lowering interleukin-18 production, but promoting nuclear factor erythroid-2-related factor-2 (Nrf2) activation; (3) EGCG had prophylactic effects on lupus nephritis in NZB/W F1 mice that are highly associated with its effects of enhancing the Nrf2 antioxidant signaling pathway, decreasing renal NLRP3 inflammasome activation, and increasing systemic regulatory T cell activity. Therefore, DCB-SLE1, antroquinonol, and EGCG have the potential to develop as therapeutic agents or adjuvants for the prevention and treatment of lupus nephritis in the future.

壹、緒論
一、紅斑性狼瘡（systemic lupus erythematosus, SLE）…………………………1
二、狼瘡腎炎（lupus nephritis）………………………………………………2
（一）狼瘡腎炎的病理分型…………………………………………………… 2
（二）惡化型狼瘡腎炎 (severe lupus nephritis)………………………………. 3
（三）狼瘡腎炎的致病機轉……………………………………………………3
三、自由基(free radicals)與活性氧(reactive oxygen species, ROS)……………6
四、Nrf2（nuclear factor-erythroid-2-related factor 2）抗氧化路徑…………… 7
五、NLRP3發炎體 (NLRP3 inflammasome)………………………………… 8
六、DCB-SLE1簡介………………………………………………………………9
七、Antroquinonol，牛樟芝純化物之簡介…………………………………11
八、沒食子酸酯化兒茶素(epigallocatechin-3-gallate, EGCG) 之簡介……12
九、研究動機與目的…………………………………………………………12
貳、實驗材料與方法
一、動物模式及實驗設計…………………………………………………14
二、尿蛋白與腎功能之偵測………………………………………………15
三、組織型態學分析………………………………………………………15
四、血清中自體抗體及補體（complement component）之偵測……………16
五、免疫螢光（immmunofluorescence）及免疫組織化學染色（immuohistochemistry staining）………………………………………………………………16
六、利用流式細胞分析儀（Flow Cytometry）分析T細胞、B細胞及調節性T細胞活化情形……………………………………………………………18
七、T細胞的增生實驗（T cell proliferation assay）…………………………18
八、調節性T細胞功能分析………………………………………………18
九、自然殺手細胞（natural killer cell）活性偵測…………………………19
十、血清中細胞激素之偵測………………………………………………19
十一、腎臟組織即時聚合酶鏈鎖反應（real-time PCR）……………………20
十二、蛋白質萃取及西方墨點法（Western blot）…………………………20
十三、腎組織中NF-κB p65 活性偵測……………………………………………21
十四、TUNEL（terminal deoxy-nucleotibyl transferase-mediated dUTP-biotin nick end labelling）染色偵測細胞凋亡……………………………………………21
十五、血液、尿液及組織中ROS偵測……………………………………………22
十六、腎臟中GPx活性分析………………………………………………………22
十七、統計分析……………………………………………………………………22
叁、結果
Part I、DCB-SLE1改善加速惡化型狼瘡腎炎小鼠動物模式………………………23
一、DCB-SLE1降低加速惡化型狼瘡腎炎之蛋白尿及血尿，改善腎功能及腎組織損傷…………………………………………………………………………23
二、DCB-SLE1降低血清中自體抗體濃度及腎臟上免疫複合物之沉積………23
三、DCB-SLE1抑制腎臟中T細胞、巨噬細胞及中性球之浸潤…………………24
四、DCB-SLE1降低腎臟中IL-6、IL-17A及IL-18 mRNA表現…………………24
五、DCB-SLE1抑制腎臟中IL-6及MCP-1蛋白質表現及NF-κB活性……………25
六、DCB-SLE1降低抑血液中發炎細胞激素之表現…………………………… 25
七、DCB-SLE1調控細胞免疫反應………………………………………………25
Part II、牛樟芝純化物antroquinonol改善加速惡化型狼瘡腎炎小鼠動物模式…28
一、Antroquinonol降低加速惡化型狼瘡腎炎之蛋白尿及血尿產生並保護腎功能……………………………………………………………………………28
二、Antroquinonol改善嚴重的腎組織損傷……………………………………….28
三、Antroquinonol調節全身免疫反應……………………………………………29
四、Antroquinonol抑制發炎細胞激素之表現……………………………………30
五、Antroquinonol減少腎臟中發炎細胞之浸潤…………………………………31
六、Antroquinonol降低ROS生成並增強Nrf2抗氧化訊息傳遞路徑……………32
Part III、EGCG減緩狼瘡腎炎小鼠動物模式之發生………………………………34
一、EGCG改善紅斑性狼瘡小鼠蛋白尿、腎功能及腎組織病變…………………34
二、EGCG降低ROS含量、增加GPx活性並活化Nrf2訊息傳遞路徑…………34
三、EGCG經由降低NF-κB活化改善腎臟中T細胞及巨噬細胞浸潤情形……………………………………………………………………………36
四、EGCG降低血清中發炎細胞激素IL-1β 及IL-18含量………………………36
五、EGCG抑制NLRP3 inflammasome活化………………………………………36
六、EGCG抑制全身免疫並增加Treg細胞活性…………………………37
肆、討論
一、全身免疫調節…………………………………………………………………39
二、發炎反應………………………………………………………………………40
三、抗氧化路徑……………………………………………………………………42
伍、結論………………………………………………………………………………44
陸、參考文獻…………………………………………………………………………45
表……………………………………………………………………………………66
圖……………………………………………………………………………………67

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