龍膽瀉肝湯對紅斑性狼瘡小鼠之調控機制研究(全程總報告)

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Abstract

全身性紅斑性狼瘡是一種慢性、多器官侵蝕、系統的發炎性,它和免疫系統失調及廣泛性地免疫複合體沈積有關,同時可以見到細胞激素和發炎細胞共同產生的炎症反應。其病理機轉最主要是導因於身體所產生不同種類的自體抗體,以致於造成身體各個系統及器官的功能喪失會危及生命的疾病。龍膽瀉肝湯是中醫臨床最常用的清熱瀉火劑之一,原為瀉肝膽實火、清下焦溼熱而設,但目前所使用的範圍則越來越廣,既廣被報導具有抑制脂質過氧化的作用,又兼具免疫調節的功能,但真正在實驗性紅斑性狼瘡的作用機制卻一直缺乏科學性的探討。本計劃以MRL lpr/lpr 小鼠為自發性的自體免疫疾病動物模式,小鼠在長大的過程中會出現類似人類全身性紅斑性狼瘡的症狀。實驗動物與以餵食龍膽瀉肝湯與龍膽草正丁醇萃取物二週後,收集血液與腎臟組織進行病理檢驗與免疫分析。實驗結果發現,龍膽瀉肝湯可以降低紅斑性狼瘡小鼠體內的氧化壓力,也確實改善了紅斑性狼瘡小鼠外觀脫毛潰爛發炎的現象。龍膽瀉肝湯對改善MRL 小鼠有嚴重的腎膈增生,腎臟組織IgG 染色沉積較輕。蛋白質體研究各組間有變化的標誌蛋白與腎臟滲透壓調控有密切的關係。有趣的是龍膽瀉肝湯治療後整個腎臟組織氧化壓力下降,抗氧化能力明顯提升。MRL小鼠呈現明顯的脾臟腫大的現象,餵食龍膽瀉肝湯的小鼠脾臟明顯縮小,我們分析此作用與脾臟中調節性T 細胞的表現有關。這項優勢也表現在龍膽瀉肝湯介入紅斑性狼瘡小鼠MRL-lpr/lpr 治療,顯著降低血中Anti-dsDNA、TNF-α 與IFN-γ 的濃度。上述之研究結果在龍膽草正丁醇萃取物餵食組有類似的表現。藉由此研究,我們希望能進一步評估龍膽瀉肝湯具有治療人類全身性紅斑性狼瘡的潛力。
Systemic lupus erythematosus (SLE) is a chronic multisystem disorder of presumed autoimmune origin in which cytotoxic antibodies, or circulating immune complexes, give rise to tissue damage often resulting in end organ disease and even mortality. Longdan Xiegan Tang (LXT) is a herbal medicine with purge gandanshihou (瀉肝膽實火) and clear xiajiaoshire (清下焦濕熱) effects. In addition, which has significant effect on oxygen free radicals and lipid peroxidation. In the present study we investigate its immunomodulatory effect on inhibiting autoimmune disease in MRL lpr/lpr mice. MRL lpr/lpr mice treats daily with LXT or 1-butanol extract of Gentianae Radix for 2 weeks. Histologic analysis of kidney tissue indicated that LXT could inhibit the mesangial proliferation that was evident in lupus nephritis. In addition LXT could promote antioxidant enzyme levels in kidney tissue of MRL mice. LXT restored cellular reduced glutathione levels, thereby limit the oxidative stress which is overproduction in MRL/lpr mice. In addition, LXT activated Treg and eliminated activated T lymphocytes responsible for lymphoproliferation and skin and kidney lesions, leading to significantly prolonged survival rates. This treatment also markedly reduced anti-ds-DNA autoantibody, IFN-g, TNF-a and IgG immune-complex deposition in kidney tissue. The protein expression profiles in kidney tissue that are associated with the physiological and pathological change of osmotic pressure during SLE progression be analyzed by two-dimension gel electrophoresis and image analysis. Similar therapeutic effects also response to 1-butanol extract of Gentianae Radix treatment mice. The study would fill a long-existing gap in Chinese medicine in the pathophysiological disorder of SLE. It may also lead to the discovery of potentially useful herb drugs for treating SLE in human patients.
Original languageChinese (Traditional)
Pages (from-to)159-191
Journal行政院衛生署中醫藥年報
Volume29
Issue number8
StatePublished - 2011

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