臺灣博碩士論文加值系統

敗血症為細菌感染之後造成的全身性免疫反應，內毒素為誘發敗血症的重要因子。體內的免疫系統在內毒素刺激下發生過度反應，細胞激素以及自由基大量形成，影響正常的生理功能，而對體細胞和臟器產生攻擊而受損，最後導致多重器官衰竭、瀰漫性凝血，以及死亡。熱休克蛋白90和許多疾病相關的蛋白具有交互作用，若能有效的抑制熱休克蛋白90能有效的改善如癌症等相關的疾病。熱休克蛋白70為體內重要的保護因子之一，在疾病發生時能有效的對抗自由基以及細胞激素的攻擊。本論文利用兩種不同的熱休克蛋白90抑制劑進行研究。Celastrol (雷公藤紅素) 為中草藥雷公藤的根部萃取物之一，具有抗氧化及抗發炎的能力，可有效抑制熱休克蛋白90與其伴隨蛋白cdc37的交互作用，已常被使用於發炎相關的病症，例如：退化性關節炎以及癌症相關的研究上。本實驗中將麻醉的Wistar公鼠由靜脈注射內毒素LPS (10 mg/kg)，Celastrol預處理組 (0.5及 1 mg/kg) 於內毒素給予前兩小時，治療組 (1 mg/kg) 則於內毒素給予三十分鐘後由靜脈注射給予。實驗結果發現，在內毒素誘發敗血症八小時之後，Celastrol處理的組別都可以回復因內毒素血症造成的低血壓和心跳下降，保護血管並維持其血管功能。因內毒素血症造成上升的ALT、BUN、LDH可以有效的被降低。血管中的超氧陰離子以及心臟中的GSH含量在預先給予Celastrol的組別皆有改善的效果。HO-1和HSP70的組織蛋白中的表現量有上升的情形。iNOS的表現量在給予Celastrol的組別可抑制其表現，透過抑制NF-kappa B中p65磷酸化的比例，造成NO的產量下降，減少血壓下降的影響及自由基的風險。在免疫方面，Celastrol可有效抑制血漿中及組織由LPS所誘發的TNF-α濃度，達到抗發炎的效果。Celastrol可有效抑制內毒素所造成的Caspase 3活性上升，達到抗凋亡作用。另一熱休克蛋白90抑制劑為17-DMAG，可抑制熱休克蛋白90的ATP水解酶活性，而有效的增加熱休克蛋白70的表現量。因此第二部份實驗目的在探討由內毒素誘發嚴重內毒素血症暨瀰漫性凝血之模式中17-DMAG的抗氧化、抗發炎、抗凋亡，以及抗凝血功能。本實驗模式將麻醉的Wistar公鼠以內毒素LPS (30 mg/kg) 持續靜脈注射四小時，並於六小時為實驗終點。17-DMAG (5 mg/kg) 則於LPS給予前二十小時腹腔注射給藥。實驗結果顯示：當給予17-DMAG時，相較於LPS组，能有效預防改善肝、腎功能，降低肝臟損傷、肺臟嗜中性球浸潤及減少血漿中TNF-α和IL-6上升。此外，給予17-DMAG處理組顯著的縮短凝血時間的延長及減少肺臟中PAI-1蛋白表現，明顯改善血小板數目的減少。在心臟組織中的超氧陰離子下降，增加GSH含量。給予LPS 六小時後，組織中iNOS表現與血中NO濃度均上升，但在給予17-DMAG處理有顯著減少。17-DMAG可有效降低內毒素所造成的Caspase 3活性上升，而達到抗凋亡作用。17-DMAG減少細胞激素IL-6釋放、抑制Caspase 3活性及降低 iNOS/NO表現等作用可被熱休克蛋白HSP70抑制劑 Quercetin 所拮抗。本篇結論，在內毒素血症大鼠模式中，熱休克蛋白90抑制劑可改善多重器官功能、具抗氧化、抗凋亡、以及抗發炎作用，此可能與誘導熱休克蛋白70 及 HO-1 生成有關。

Sepsis is a systemic inflammatory disorder, accompanied with elevated oxidative stress, leading to multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulation (DIC). HSP90 is one chaperone protein to refold the abnormal proteins. HSP90 has been reported to be up-regulated in different diseases. HSP90 inhibitors were reported to possess anti-inflammatory effects, associated with activation of the HSF-1, leading to induction of HSP70 production. HSP70 is another chaperone protein among all organs. HSP70 can refold the misfolding or unfolding proteins. HSP70 plays an important role in maintaining cellular homeostasis to defend organs from bacterial infection and acute inflammation-evoked damages. In this study, we evaluated benefical effects of two HSP90 inhibitors, celastrol and 17-Dimethyl-aminoethylamino- 17-demethoxygeldanamycin (17-DMAG) on sepsis induced by lipopolysaccharide (LPS) in rats. Celastrol, a quinone methide extracted from the root of Tripterygium wilfordii Hook, possesses anti-oxidant and anti-inflammatory effects. Celastrol (0.5 and 1.0 mg/kg, i.v.) was administered to anaesthetized rats 2 h before or 30 min after LPS challenge (10 mg/kg, i.v.). Eight hours later, cardiac and aortic protein expression related to inflammatory responses, superoxide anion production, and reduced glutathione (GSH) level were measured. Treatment with celastrol prevented circulatory failure (bradycardia and hypotension) 8 h after LPS challenge. The plasma levels of ALT, LDH, TNF-α, and nitric oxide (NO) metabolites were increased markedly during sepsis, which significantly reduced after celastrol treatments. Celastrol attenuated iNOS, TNF-α, NF-κB phospho-p65 expression, superoxide anion production, and caspase 3 activity in the cardiovascular system, all of which were markedly elevated after LPS challenge. Furthermore, celastrol induced HO-1 and HSP70 expression via increases in nuclear levels of Nrf2 and HSF-1, respectively, and increased the levels of reduced form of glutathione (GSH) in heart 8 h after LPS challenge. On the other hand, 17-DMAG, an HSP 90 inhibitor, has been reported to possess anti-inflammatory effects. In this study, the beneficial effects of 17-DMAG on MODS and DIC induced by LPS (30 mg/kg i.v. infused for 4 h) were evaluated in anesthetized rats. Pretreatment with 17-DMAG (5 mg/kg, i.p.) 20 h prior to LPS initiation significantly increased survival rate, and prevented hypotension 6 h after LPS initiation. Plasma levels of ALT, CPK, LDH, CRE, NO metabolites, IL-6, and TNF-α significantly elevated 2 or 6 h after LPS initiation, all of which were significantly reduced by 17-DMAG. 17-DMAG suppressed superoxide anion production and caspase 3 activation caused by LPS, and increased the levels of GSH in heart. LPS induced a pronounced decrease in platelet count and the prolongation of prothrombin time, which were improved by 17-DMAG. 17-DMAG markedly induced HSP70 and HO-1, and suppressed iNOS protein expression in livers, lungs, and/or hearts 6 h after LPS initiation. Pretreatment with high dose of quercetin (400 mg/kg, i.p.), as an HSP70 inhibitor 6 h prior to LPS given, reversed the beneficial effects of 17-DMAG on plasma levels of ALT, CPK, CRE, IL-6, and NO metabolites, iNOS induction and caspase-3 activation. In conclusion, celastrol and 17-DMAG possess the anti-inflammatory and antioxidant effects on LPS-induced acute inflammation, which is associated with induction of HSP70 and HO-1, leading to prevent MODS in sepsis. HSP90 inhibitors might be considered as a novel therapeutic strategy in prevention of sepsis-induced MODS.

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目錄 I
圖表目錄 V
中文摘要 XII
英文摘要 XV
第一章 緒言
第一節 敗血症及敗血性休克簡介 1
第二節 內毒素引起的敗血症之致病機轉 1
第三節 熱休克蛋白 3
第四節 細胞激素、發炎和內毒素血症之間的關係 6
第五節 內毒素血症對於心血管功能的影響 8
第六節 內毒素血症與瀰漫性血管內凝血反應 8
第七節 NO/iNOS與內毒素血症之間的關係 9
第八節 CO/HO-1與內毒素血症之間的關係 10
第九節 Celastrol簡介及其相關研究 11
第十節 17-DMAG簡介及其相關研究 12
第十一節 動物模式 14
第二章 實驗目的 15
第三章 材料與方法 16
第一節 實驗藥品與其來源 16
第二節 活體實驗 19
第三節 活體外 (ex vivo) 實驗 28
第四節 數據分析 39
第四章 實驗結果
第一部分：雷公藤紅素 (Celastrol) 與內毒素血症
第一節 Celastrol 對內毒素血症之血流動力學影響 40
第二節 Celastrol 對內毒素血症引起器官功能異常之影響 41
第三節 Celastrol對LPS引起細胞激素TNF-α含量變化 44
第四節 Celastrol對LPS引起之自由基及氧化壓力的影響 45
第五節 Celastrol對LPS引起ㄧ氧化氮 (NO) 生成量增加的影響 46
第六節 Celastrol 對 LPS 引起各種蛋白質表現之影響 47
第七節 Celastrol對LPS引起之血糖變化之影響 50
第八節 存活率分析 51
第二部分：17-DMAG與內毒素血症
第一節 17-DMAG對LPS造成血流動力學變化之影響 51
第二節 17-DMAG對LPS引起器官功能異常之影響 53
第三節 17-DMAG對LPS引起血中NO生成量增加的影響 55
第四節 17-DMAG對LPS引起體內細胞激素含量之影響 56
第五節 17-DMAG對LPS引起之自由基及氧化壓力的影響 57
第六節 17-DMAG對LPS引起之瀰漫性凝血現象之影響 58
第七節 17-DMAG對LPS引起各種蛋白質表現之影響 59
第八節 由組織切片觀察17-DMAG對LPS引起之肝肺臟損傷
及發炎情形 61
第九節 存活率分析 62

第五章 討論
第一部分 Celastrol 對於大鼠內毒素血症的影響 63
第一節 LPS 造成循環系統損傷及其機轉 63
第二節 Celastrol 對於循環系統的保護機轉 64
第三節 Celastrol 改善內毒素血症所造成的多重器官衰竭 65
第四節 Celastrol 對大鼠內毒素血症所造成的發炎情形之
抑制可能機轉 68
第五節 Celastrol對大鼠內毒素血症所造成的氧化壓力之
抑制可能機轉 69
第二部分 17-DMAG 對於大鼠內毒素血症的影響 69
第一節 17-DMAG對於發炎反應的保護機轉 70
第二節 17-DMAG 對於凝血系統的保護機轉 71
第三節 17-DMAG 改善內毒素血症所造成的多重器官衰竭 72
第四節 17-DMAG 對大鼠內毒素血症所造成的心臟組織
凋亡情形之抑制可能機轉 74
第五節17-DMAG對大鼠內毒素血症所造成的氧化壓力之
抑制可能機轉 75
第六章 結論 76
第七章 未來展望 77
參考文獻 124










表目錄
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Table 1. Effects of celastrol (Cel) on blood glucose (BG) in rats
with sepsis induced by LPS challenge 78





















圖目錄
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Fig. 1-1. Effects of celastrol (Cel) on mean arterial blood pressure (MAP) in rats with sepsis induced by LPS challenge. 79

Fig. 1-2. Effects of celastrol (Cel) on heart rate in rats with sepsis
induced by LPS challenge 80

Fig. 1-3. Effects of celastrol (Cel) on rate-pressure product in rats
with sepsis induced by LPS challenge 81

Fig. 1-4. Effects of celastrol (Cel) on norepinephrine (NE)-elicited
pressor response in rats with sepsis induced by LPS
challenge 82

Fig. 1-5. Effects of celastrol (Cel) on vascular reactivity in rats with
sepsis induced by LPS challenge 83

Fig. 1-6. Effects of celastrol (Cel) on caspase 3 activity in heart
tissue in rats with sepsis induced by LPS challenge 84

Fig. 1-7. Effects of celastrol (Cel) on plasma levels of alanine
aminotransferase (ALT) in rats with sepsis induced by
LPS challenge 85

Fig. 1-8. Effects of celastrol (Cel) on plasma levels of lactate dehydrogenase (LDH) in rats with sepsis induced by LPS challenge 86

Fig. 1-9. Effects of celastrol (Cel) on plasma levels of blood urea
nitrogen (BUN) in rats with sepsis induced by LPS
challenge 87

Fig. 1-10. Effects of celastrol (Cel) on plasma concentration of
TNF- expression 8 h after LPS challenge in rats 88

Fig. 1-11. Effects of celastrol (Cel) on cardiac TNF- proteins
expression 8 h after LPS challenge in rats 89

Fig. 1-12. Effects of celastrol (Cel) on aortic TNF-α proteins
expression 8 h after LPS challenge in rats 90

Fig. 1-13. Effects of celastrol (Cel) on superoxide anion production
in aorta 8 h after LPS challenge in rats 91

Fig. 1-14. Effects of celastrol (Cel) on reduced form of glutathione
(GSH) expression (A) and GSH/GSSG ratio (B) in the
heart 8 h after LPS challenge in rats 92

Fig. 1-15. Effects of celastrol (Cel) on plasma levels of NO
metabolites 8 h after LPS challenge in rats 93

Fig. 1-16. Effects of celastrol (Cel) on iNOS protein expression in
heart 8 h after LPS challenge in rats 94

Fig. 1-17. Effects of celastrol (Cel) on iNOS protein expression in
aorta 8 h after LPS challenge in rats 95

Fig. 1-18. Effects of celastrol (Cel) on phospho-p65 protein expression in heart 8 h after LPS challenge in rats. 96

Fig. 1-19. Effects of celastrol (Cel) on HO-1 protein expression in
heart 8 h after LPS challenge in rats 97

Fig. 1-20. Effects of celastrol (Cel) on HO-1 protein expression in
aorta 8 h after LPS challenge in rats 98

Fig. 1-21. Effects of celastrol (Cel) on nuclear Nrf2 protein expression in aorta 8 h after LPS challenge in rats 99

Fig. 1-22. Effects of celastrol (Cel) on HSP70 protein expression in
heart 8 h after LPS challenge in rats 100

Fig. 1-23. Effects of celastrol (Cel) on HSP70 protein expression in
aorta 8 h after LPS challenge in rats 101
Fig. 1-24. Effects of celastrol (Cel) on nuclear HSF-1 protein
expression in aorta 8 h after LPS challenge in rats 102

Fig. 2-1. Effects of 17-DMAG (17D) on mean arterial blood pressure (MAP) in rats with endotoxemia induced by LPS injection 103

Fig. 2-2. Effects of 17-DMAG (17D) on heart rate (HR) in rats with endotoxemia induced by LPS injection 104

Fig. 2-3. Effects of 17-DMAG (17D) on alanine aminotransferase (ALT) in rats with endotoxemia induced by LPS injection 105

Fig. 2-4. Effects of 17-DMAG (17D) on creatine phosphokinase (CPK) in rats with endotoxemia induced by LPS injection 106

Fig. 2-5. Effects of 17-DMAG (17D) on lactate dehydrogenase (LDH)
in rats with endotoxemia induced by LPS injection 107

Fig. 2-6. Effects of 17-DMAG (17D) on the changes of creatinine
(ΔCRE) in rats with endotoxemia induced by LPS injection 108

Fig. 2-7. Effects of 17-DMAG (17D) on caspase 3 activity in heart
of rats 6 hours after being subjected to LPS administration 109

Fig. 2-8. Effects of 17-DMAG (17D) on plasma NO concentration
6 h after LPS injection in rats 110

Fig. 2-9. Effects of 17-DMAG (17D) on plasma TNF-α concentration
2 h after LPS initiation in rats 111

Fig. 2-10. Effects of 17-DMAG (17D) on plasma IL-6 concentration
6 h after LPS initiation in rats 112

Fig. 2-11. Effects of 17-DMAG (17D) on superoxide anion production
in heart of rats 6 h after LPS initiation 113

Fig. 2-12. Effects of 17-DMAG (17D) on glutathione expression
in heart of rats 6 hours after being subjected to LPS
administration 114

Fig. 2-13. Effects of 17-DMAG (17D) on platelet count in blood
of rats 6 h after LPS initiation 115

Fig. 2-14. Effects of 17-DMAG (17D) on prothrombin time in
blood of rats 6 h after LPS initiation 116

Fig. 2-15. Effects of 17-DMAG (17D) on PAI-1 protein
expression in lungs of rats 6 h after LPS initiation 117

Fig. 2-16. Effects of 17-DMAG (17D) on HSP70 protein
expression in heart (A), lung (B), and liver (C) of
rats 6 h after LPS initiation 118

Fig. 2-17. Effects of 17-DMAG (17D) on iNOS protein
expression in heart (A), lung (B), and liver (C) of
rats 6 h after LPS initiation 119

Fig. 2-18. Effects of 17-DMAG (17D) on HO-1 protein
expression in heart (A), lung (B), and liver (C) of
rats 6 h after LPS intiation 120

Fig. 2-19. Effects of 17-DMAG (17D) on histologic studies of
representative lung sections 121

Fig. 2-20. Effects of 17-DMAG (17D) on histologic studies of
liver sections 122
Fig. 3 Summary of HSP90 Inhibitors in Endotoxemic Rats 123

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