臺灣博碩士論文加值系統

肝臟纖維化是肝臟受到損傷時所產生之癒傷修補反應，而肝臟星狀細胞活化是肝臟纖維化病理過程中的關鍵因素。活化態星狀細胞可接受許多細胞激素的刺激，且為肝纖維化過程中纖維膠原蛋白的主要來源。近來許多研究指出氧化性壓力可直接活化星狀細胞並引發肝臟纖維化。丹參主成分之一的丹參酚酸B (Salvianolic acid B, 以下簡稱SA-B)，已被證實具有良好抗氧化活性及肝細胞保護效果；萃取自粉防己的粉防己鹼已被證實具有良好抗發炎活性。本論文以離體及活體模式探討富含SA-B 之丹參萃取物與粉防己鹼對於肝臟星狀細胞活化及大鼠肝臟纖維化的影響，並深入探討其作用機轉。
離體試驗以轉型生長因子-β1（TGF-β1）刺激大鼠肝臟星狀細胞株 (HSC-T6)活化為模式，結果發現富含SA-B 之丹參萃取物 (200 及400 μg/ml) 可顯著減少TGF-β1 誘發之Smad 2/3 蛋白質磷酸化並抑制其進入細胞核內；富含丹參酚酸B 之丹參萃取物 (200 及400 μg/ml)可抑制TGF-β1 所引發之促纖維化相關基因表現，包括: α-平滑肌肌動蛋白 (α-SMA) 、結締組織生長因子 (CTGF) 與基質金屬蛋白分解組織內抑制子第一型 (TIMP-1) ，及α-SMA 的蛋白質表現。粉防己鹼 (0.5 - 5.0 μM) 亦可顯著減少TGF-β1 所引發之細胞外膠原蛋白沉積與細胞α-SMA 的蛋白質表現。
利用reporter gene assay，以腫瘤壞死因子-α (TNF-α) 刺激
HSC-T6 細胞一天後，可使細胞NFκB 活性增加249 ± 28%，結果顯
示粉防己鹼可在更低濃度 (5.0 μM) 比SA-B (100 μM) 及富含SA-B
之丹參萃取物 (200 μg/ml)有效抑制NFκB 之活性至99 ± 34%。本研
究證實粉防己鹼可顯著抑制TNF-α 所誘發之NFκB 訊息傳導過程中
IKK-α 表現、IκB-α 磷酸化與降低細胞間黏附分子第一型 (ICAM-1)
之基因表現。進ㄧ步研究粉防己鹼抑制NFκB 之作用機轉，發現粉防
己鹼 (5.0 μM) 處理HSC-T6 細胞24 小時後，可誘發細胞內
metallothionein 之基因表現為未處理之細胞的147 ± 3%，由於
metallothionein 已被證實具有抗NFκB 活化及抗纖維化之作用，此一發現顯示粉防己鹼抑制細胞內NFκB 活化之作用可能部份藉由
metallothionein 之產生達成。
活體實驗以二甲基亞硝胺(Dimethynitrosamine，DMN)誘發大鼠
肝臟纖維化為模式。分別針對富含SA-B 之丹參萃取物與粉防己鹼進
行兩次動物試驗。實驗結果(一)顯示，胃管給予富含SA-B 之丹參萃
取物20 mg/kg 及100 mg/kg 體重之DMN 大鼠肝纖維化程度顯著降
低。富含SA-B 之丹參萃取物100 mg/kg 可顯著減少DMN 大鼠之
AST、ALT，減少DMN 大鼠肝臟內膠原蛋白之含量及抑制肝臟內促
纖維化相關基因之表現，包括α-SMA、 TGF-β1 及procollagens。實
驗結果(二)顯示，給予粉防己鹼5 mg/kg 可顯著降低 DMN 大鼠之肝
纖維化程度，粉防己鹼可顯著降低DMN 大鼠之AST、ALT，抑制
DMN 大鼠肝臟內膠原蛋白之含量，抑制肝臟內促纖維化相關基因之
表現，包括α-SMA、TGF-β1 及 ICAM-1，並提升肝臟內抗纖維化基
因metallothionein 表現。免疫螢光雙重染色實驗顯示，粉防己鹼可減少DMN 大鼠肝臟內活化態星狀細胞及其NFκB 之活化。
研究結果顯示，富含SA-B 之丹參萃取物可抑制TGF-β1 誘發之
肝臟星狀細胞活化，並可誘發抗纖維化基因MMP-13 之表現，改善
大鼠肝臟纖維化；粉防己鹼可抑制TNF-α 誘發肝臟星狀細胞之促發
炎作用，可顯著誘發抗NFκB 活化之基因metallothionein 之表現，並更有效抑制轉錄因子 NFκB 之活化與抑制NFκB 相關分子轉錄路徑，進而降低ICAM-1 的表現，並改善大鼠肝臟纖維化。綜言之，本研究利用肝臟星狀細胞株及肝纖維化動物模式探討丹參與粉防己鹼之抑制肝臟纖維化之效果與作用機轉，研究結果所提出之丹參與粉防
己鹼抑制肝臟纖維化之機轉與療效可提供未?藥物開發及中醫藥治
療肝臟纖維化之臨床應用參考。

Hepatic Fibrosis is a would-healing response during liver injury.Activation of hepatic stellate cells (HSCs) is a critical event in the pathogenesis of liver fibrosis. Activated HSCs are the predominant source of the increased extracellular matrix proteins. Excessive oxidative stress
is implicated in the activation of HSCs and hepatic fibrogenesis. Antioxidants have been proposed to inhibit the activation of HSCs and attenuate hepatic fibrosis. Salvianolic acid B (SA-B), an active component of Salvia miltiorrhiza, has been proved to exerted antioxidative activity and hepatoprotective effects. Tetrandrine (Tet), a
bis-benzyl isoquinoline alkaloid derived from Stephania tetrandra, has been proved to exerted anti-inflammatory effects. This thesis study has investigated the in vitro and in vivo anti-fibrotic effects of a SA-B-enriched extract of Salvia miltiorrhiza (SA-B-Sm) and Tet.
A hepatic stellate cell line of rat origin (HSC-T6), which could be activated by TGF-β1 or TNF-α, was used as a cellular model. SA-B-Sm (200 and 400 μg/ml) significantly reduced TGF-β1-induced Smad 2/3 phosphorylation and nuclear translocation. SA-B-Sm (200 and 400 μg/ml)
inhibited TGF-β1-stimulated α-smooth muscle actin (α-SMA) secretion, SA-B-Sm (200 and 400 μg/ml) also inhibited mRNA expressions of fibrosis-related genes, including α-SMA, CTGF, and TIMP-1 in TGF-β1-stimulated HSC-T6 cells. SA-B-Sm (400 μg/ml) was shown to increase the mRNA expression of MMP-13, which is responsible for degrading the fibrillar collagen. SA-B-Sm and Tet concentration-dependently inhibited the increase of NFκB transcriptional activity
induced by TNF-α. However, Tet exerted better potency than SA-B-Sm in anti-NFκB effects. Tet was further shown to reduce TNF-α-induced IKKα expression, IκBα phosphorylation, and attenuated TNF-α-stimulated
mRNA expression level of ICAM-1 in HSC-T6 cells. Furthermore, Tet (5.0 μM) could significantly increase the mRNA expression of metallothionein to 147 ± 3% of untreated cells. Metallothionein is reported to exert anti-NFκB and anti-fibrosis effects. The in vitro study suggested that the anti-NFκB activity of Tet might act via the induction of metallothionein. Tet (0.5-5.0 μM) also inhibited TGF-β1-induced α-SMA secretion and collagen deposition in HSC-T6 cells.Fibrosis was induced by DMN administration in rats. We performed two animal experiments to investigate the in vivo effects of SA-B-Sm and Tet on hepatic fibrosis. (I) SA-B-Sm 20 mg/kg and 100 mg/kg significantly reduced the fibrosis scores of livers from DMN rats. SA-B-Sm significantly reduced levels of plasma AST and ALT activities, hepatic collagen contents and mRNA expression levels of α-SMA,TGF-β1, procollagen I and III genes in DMN rats. (II) Tet 5 mg/kg significantly reduced the fibrosis scores of livers from DMN rats. Tet significantly reduced levels of plasma AST and ALT activities, hepatic
collagen contents and mRNA expression levels of α-SMA, TGF-β1, ICAM-1 in DMN rats. Interestingly, Tet induced the mRNA expression of metallothionein gene in DMN rats, and this is a novel mechanism of Tet to exert the anti-NFκB and anti-fibrosis effects.
In conclusion, results from this thesis study suggested that both SA-B-Sm and Tet could exert anti-fibrotic effects in the cellular and animal models of liver fibrosis. The different anti-fibrotic effects and mechanism of actions between SA-B-Sm and Tet in HSC-T6 cells and DMN-intoxicated rats might provide suggestions in drug development and clinical application of Salvia miltiorrhiza and Stephania tetrandra.

摘要-----------------------------------------------------.1
ABSTRACT--------------------------------------------------5
ABBREVIATIONS---------------------------------------------8
1. INTRODUCTION------------------------------------------11
1.1 The Liver--------------------------------------------11
1.2 General Aspects of Liver Fibrosis and Cirrhosis------11
1.3 Pathophysiology of Liver Fibrosis and Cirrhosis------12
1.3.1 Hepatic stellate cells (HSCs) in liver fibrosis and cirrhosis------------------------------------------------12
1.3.2 NFκB and the activation of HSCs--------------------15
1.3.3 Fibrogenesis and TGF-β-----------------------------16
1.3.4 Specific involvement of oxidative stress in fibrogenesis---------------------------------------------19
1.3.5 Vascular changes and angiogenesis in liver fibrosis and cirrhosis--------------------------------------------20
1.4 Reversibility of Liver Fibrosis and Cirrhosis--------21
1.5 Potential Anti-fibrotic Strategies-------------------22
1.5.1 To cure the primary disease------------------------22
1.5.2 To reduce inflammation and immune response in the liver----------------------------------------------------23
1.5.3 To inhibit HSCs activation-------------------------23
1.5.4 To neutralize proliferative, fibrogenic, contractile and/ or pro-inflammatory responses of HSCs---------------24
1.5.5 To stimulate HSCs apoptosis------------------------26
1.5.6 To increase the degradation of scar matrix---------26
1.6 Current Treatments for Liver Fibrosis and Cirrhosis--26
1.6.1 Treatments of fibrosis and cirrhosis in traditional Chinese medicine-----------------------------------------27
1.6.2 Current treatments of fibrosis and cirrhosis in Western medicine-----------------------------------------29
1.7 Current Cellular and Animal Models of Liver Fibrosis-30
1.7.1 Cellular models------------------------------------30
1.7.2 Animal models--------------------------------------32
1.8 Anti-fibrotic Potential of Plant-Derived Antioxidants and Chinese Herbal Medicines-----------------------------39
1.8.1 Salvia miltiorrhiza (Sm) --------------------------39
1.8.2 Tetrandrine (Tet) ---------------------------------43
1.8.3 Silymarin------------------------------------------46
1.8.4 Curcumin-------------------------------------------47
1.8.5 EGCG-----------------------------------------------48
1.8.6 Glycyrrhizin---------------------------------------49
1.8.7 Sho-saiko-to---------------------------------------50
1.8.8 Inchin-ko-to (TJ-135) -----------------------------51
1.9 Rationale, Experimental Models, and Approaches of This Study----------------------------------------------------52
2. MATERIALS AND METHODS---------------------------------55
2.1 Instrument-------------------------------------------55
2.2 Materials--------------------------------------------55
2.3 Animals and HSC-T6 Cell Line-------------------------57
2.4 Methods----------------------------------------------58
2.4.1 Preparation SA-B enriched extract of Sm and HPLC profile--------------------------------------------------58
2.4.2 Cell viability assay-------------------------------58
2.4.3 Reporter gene assay--------------------------------59
2.4.4 Western blot analyses------------------------------60
2.4.5 Hepato-fibrotic animals (DMN models) --------------61
2.4.6 Histopathological examination----------------------62
2.4.7 Biochemical analysis of plasma---------------------63
2.4.8 Immuno-fluorescence double staining----------------64
2.4.9 Semi-quantitative RT-PCR---------------------------65
2.4.10 Quantitative real-time PCR------------------------67
2.4.11 Quantification of collagen deposition-------------68
2.4.12 Statistical analyses------------------------------69
3. RESULTS-----------------------------------------------70
3.1 Anti-fibrotic mechanisms of SA-B-Sm and Tetrandrine on HSC-T6 cells --------------------------------------------70
3.1.1 Effects of TGF-β1 on the activation of HSC-T6 cells------------------------------------------------------------70
3.1.2 NFκB activation in HSC-T6 cells--------------------70
3.1.3 Effects of Sm and Tet on TGF-β1-induced HSC-T6 cells activation------------------------------------------------71
3.1.4 Effeects of Sm and Tet on TNFα-induced NFκB signaling cascade in HSC-T6 cells-------------------------72
3.2 Increases of Fibrosis-Related Markers in the Livers of DMN- Intoxicated Rats-------------------------------------73
3.3 Effects of Sm and Tet on DMN-Intoxicated Rats---------76
3.3.1 Anti-fibrotic effects of Sm on DMN-intoxicated rats-76
3.3.2 Anti-fibrotic effects of Tet on DMN-intoxicated rats------------------------------------------------------------79
4. DISCUSSION---------------------------------------------82
4.1 Anti-fibrotic mechanisms of SA-B-Sm in HSC-T6 cells---82
4.2 Anti-fibrotic effects of SA-B-Sm on DMN-intoxicated rats -----------------------------------------------------84
4.3 Anti-fibrotic mechanisms of Tet in HSC-T6 cells-------87
4.4 Anti-fibrotic effects of Tet on DMN-intoxicated rats--90
4.5 Studies of metallothionein----------------------------91
5. CONCLUSION --------------------------------------------93
6. FUTURE DIRECTIONS--------------------------------------95
REFERENCES------------------------------------------------96
Table 1-10-----------------------------------------------125
Figure 1-35----------------------------------------------139

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