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研究生:呂佳賢
研究生(外文):LU, CHIA-HSIEN
論文名稱:熱休克蛋白90抑制劑 NVP-AUY922對內毒素血症引起的多重器官衰竭之療效評估
論文名稱(外文):The Effect of NVP-AUY922, a Novel HSP90 Inhibitor, on Multiple Organ Dysfunction in Endotoxemic Rats
指導教授:李燕媚
指導教授(外文):LEE, YEN-MEI
口試委員:沈信學蕭哲志
口試委員(外文):SHEN, HSIN-HSUEHHSIAO, GEORGE
口試日期:2019-05-16
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:中文
論文頁數:85
中文關鍵詞:熱休克蛋白90抑制劑敗血症多重器官衰竭內毒素血症
外文關鍵詞:SepsisMultiple organ dysfunctionHeat shock protein 90 inhibitorNVP-AUY922
相關次數:
  • 被引用被引用:1
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  • 下載下載:1
  • 收藏至我的研究室書目清單書目收藏:0
敗血症是因感染造成身體反應失調而引起會危及生命的多重器官功能障礙。影響敗血症的兩大病因主要是由感染病原菌造成菌血症及宿主自身免疫反應。經統計菌血症的加護病房患者中,由革蘭氏陰性菌引起的菌血症導致敗血症的發生率明顯高於其他病原菌引起的感染。在革蘭氏陰性菌的細胞壁上,具有一個脂多醣體lipopolysaccharide (LPS),又稱內毒素。身體的免疫系統在內毒素刺激下發生過度反應,細胞激素及自由基大量形成,影響正常生理功能,導致瀰漫性血管內凝血、多重器官衰竭以及死亡。本實驗室過去的研究顯示,Heat shock protein 90 (HSP90) 抑制劑17-DMAG可明顯改善敗血症引起之多重器官衰竭。HSP90 是一種伴侶蛋白,和許多會引起疾病的蛋白質有交互作用,若能抑止HSP90可有效的改善疾病,例如:癌症。HSP70為體內重要保護因子之一,在疾病發生時能對抗自由基和細胞激素的生成,抑制 HSP90 可誘導 HSP70 的生成。新一代 HSP90 inhibitor NVP-AUY922 (NVP),其結構不同於常見之HSP90 inhibitor geldanamycin 結構或其類似物,但是其效果一樣可以抑制HSP90的ATP水解酶活性,使HSP90無法活化,進而增加HSP70的表現量。在許多細胞研究上,也證實其毒性確實較低於geldanamycin或其結構類似物。本研究欲探討在嚴重內毒素血症動物模式下,預先給予 NVP 後,評估是否可改善內毒素血症所引發之多重器官衰竭,是否透過產生抗氧化、抗發炎、抗凋亡以及抗凝血的功能達到預防敗血症的效果。實驗動物區分為四組:(1) 控制組 (Control group):僅插管手術並給予生理食鹽水作為時間對照; (2) 單獨 NVP- AUY922組 (NVP group):實驗開始前19小時腹腔注射NVP 5 mg/kg,插管手術加休息時間約一個小時,即NVP 作用滿二十小時,再經由股靜脈給予生理食鹽水 9 ml,持續輸注四小時 (2.25 ml/hr),作為給藥的對照組; (3) 內毒素組 (LPS group):插管手術後由股靜脈給予LPS 30 mg/kg (溶解於9 ml生理食鹽水)持續輸注四小時 (2.25 ml/hr),以建立嚴重內毒素血症的動物模式,觀察至實驗開始後第6小時; (4) 預處理NVP-AUY 922 + 內毒素LPS 組 (NVP + LPS group):實驗開始前19小時利用腹腔注射的方式給予NVP 5 mg/kg,插管手術加休息時間約一個小時,即NVP 作用滿二十小時,再經由股靜脈給予LPS 30 mg/kg (溶解於9 ml生理食鹽水) 持續輸注四小時 (2.25 ml/hr)。實驗結果顯示:預先給予NVP時,明顯提高敗血症之存活率,改善肝腎功能異常、降低細胞毒性,減少肺臟傷害與心臟組織的凋亡;有效抑止NF-κB的發炎路徑,同時減少iNOS與發炎相關細胞激素的蛋白生成量,抑制發炎反應,並增加細胞的自噬作用,避免發炎反應進一步的傷害。此保護作用認為可能透過增加誘導產生HSP70,抑制發炎反應,進而改善嚴重內毒素血症鼠的多重器官功能異常及存活率。
Sepsis is defined as a life-threatening organ dysfunction syndrome with high morbidity and mortality caused by bacterial infection. The major characteristics of sepsis are systemic inflammatory responses accompanied with elevated oxidative stress, leading to multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulation (DIC). As a molecular chaperon to repair unfolded proteins, heat shock protein 70 (HSP 70) maintains cellular homeostasis and shows protective effects on inflammatory damage. HSP 90 inhibitors were reported to exert anti-inflammatory effects via activation of the heat shock factor-1 (HSF-1), leading to induction of HSP 70. A previous study in our laboratory has shown that HSP90 inhibitor 17-DMAG improved multiple organ function in endotoxemic rats. In this study, we evaluated the beneficial effect of novel HSP 90 inhibitor NVP-AUY 922 (NVP) on multiple organ dysfunction syndrome induced by lipopolysaccharide (LPS) and further explored the underlying mechanism. NVP (5 mg/kg, i.p.) was administered 20 h prior to LPS initiation (LPS 30 mg/kg, i.v. infusion for 4 h) in male Wistar rats. Results demonstrated that pretreatment with NVP significantly increased survival rate and prevented hypotension at 6 h after LPS administration. Plasma levels of ALT, CRE and LDH were significantly reduced by NVP at 6 h after LPS challenge. The induction of inducible NO synthase in the liver, lung and heart and NF-κB p-p65 protein expression were also attenuated by NVP. NVP also suppressed caspase 3 activation and upregulated autophage-related protein LC3-Ⅱ in organs. In addition, NVP markedly induced HSP 70 proteins in the liver, lung and heart, which still maintained in a significantly high level in endotoxemia. These results indicated that NVP possessed the anti-inflammatory effects, which might be associated with induction HSP70, leading to prevent MODS in sepsis. Further experiments are needed to explore the cause effect relationship between NVP and HSP70. HSP 90 inhibitors NVP might be considered as a novel therapeutic strategy in the prevention of sepsis-induced MODS.
致謝 I
中文摘要 III
Abstract V
目錄 VII
圖目錄 X
第一章 緒論 1
第一節、 敗血症及敗血性休克簡介 1
第二節、 內毒素引起敗血症之致病機轉 1
第三節、 細胞激素、發炎與內毒素血症之關係 3
第四節、 熱休克蛋白 4
第五節、 敗血症與自噬作用、凋亡作用 7
第六節、 NVP-AUY 922簡介及其相關研究 8
第二章 研究目的 10
第三章 材料與方法 11
第一節、 實驗藥物與其來源 11
第二節、 活體 (in vivo) 實驗 13
第三節、 實驗動物分組 14
第四節、 血糖、器官功能指標生化數值及凝血功能之檢測 15
第五節、 發炎相關cytokines的測定: 16
第六節、 嚴重內毒素血症發炎相關蛋白質的表現 17
第七節、 器官組織之病理切片 18
第八節、 數據分析 18
第四章 實驗結果 19
第一節、 NVP 對內毒素血症大鼠存活率之影響 19
第二節、 NVP 對內毒素血症大鼠血壓心跳之影響 19
第三節、 NVP對LPS引起之體溫與血糖變化之影響 20
第四節、 NVP 對LPS引起血小板數目減少之影響 21
第五節、 NVP對LPS引起肝、腎功能異常之影響 21
第六節、 NVP 對LPS引起各種細胞激素釋放之影響 22
第七節、 NVP 對LPS引起發炎路徑蛋白質表現之影響 23
第八節、 NVP 對抗發炎蛋白質表現之影響 24
第九節、 NVP 對自噬作用指標LC3-Ⅱ表現之影響 25
第十節、 NVP 對心臟凋亡指標Caspase 3表現之影響 25
第十一節、 組織切片觀察NVP對LPS引起之肺、肝臟損傷 25
第五章 討論 27
第一節、 NVP對內毒素血症大鼠生命跡象與存活率之影響 27
第二節、 NVP對內毒素血症所造成的多重器官衰竭之影響 29
第三節、 NVP對內毒素血症的抗發炎與抗氧化反應 31
第四節、 NVP改善內毒素血症造成的細胞自噬與凋亡作用 33
第五節、 NVP-AUY922與17-DMAG的比較 35
第六章 結論 37
第七章 未來展望 38
參考文獻 65

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