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研究生：	呂亮萱 Lu, Liang-Hsuan
論文名稱：	探討自噬作用作為敗血性休克治療標的之可能性 Autophagy is a potentially therapeutic target in septic shock
指導教授：	葉才明 Yeh, Trai-Ming
學位類別：	碩士 Master
系所名稱：	醫學院 - 醫學檢驗生物技術學系 Department of Medical Laboratory Science and Biotechnology
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	54
中文關鍵詞：	敗血症、高遷移率族蛋白 1 、自噬作用、血管滲漏、細胞激素、細菌清除
外文關鍵詞：	sepsis, HMGB1, autophagy, vascular leakage, cytokine, bacterial clearance
相關次數：	點閱：120 下載：1
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敗血症是因為感染而引起全身性發炎反應且致死性極高的疾病。由於血液中含有高量的發炎激素導致血管滲漏，患者往往會死於低血壓所引起的休克。然而目前仍無有效且具專一性之藥物可降低敗血症的高致死率。高遷移率族蛋白1 (High mobility group box 1, HMGB1)是一種會於敗血症晚期釋出的細胞激素，且被認為在敗血症中扮演重要角色。然而目前已知，針對細胞激素本身做抑制，並無法有效降低敗血症患者的死亡率。先前研究顯示，自噬作用(Autophagy)會參與在脂多醣(Lipopolysaccharides, LPS) 所引起的內皮細胞高通透性。此外，自噬作用也具有調控免疫細胞製造及分泌部分細胞激素如介白素-1 (interleukin 1, IL-1)及腫瘤壞死因子-α (tumor necrosis factor, TNF-α) 之能力，而抑制自噬作用也可促進巨噬細胞的吞噬作用。因此，本研究將進一步探討，抑制細胞自噬是否能降低在敗血症情況下病原菌感染及發炎反應之嚴重程度。首先，我們發現LPS誘發白血球之促發炎激素的生成會被自噬作用抑制劑所抑制。此外，由LPS條件培養液 (LPS-conditioned medium) 及HMGB1所誘發的內皮細胞通透性增加，在自噬抑制劑存在下也會被抑制。而在經自噬抑制劑處理之後的白血球，其吞噬細菌的能力會提升。最後，我們利用大腸桿菌感染小鼠引起的敗血症模式下，展示了在細菌感染後給予自噬抑制劑，可增強小鼠清除細菌的能力及降低發炎激素的產生和血管滲漏的情形，最終有效提升小鼠的存活率。以上結果說明，自噬作用在敗血症的致病機轉中扮演很重要的角色，且或許可作為敗血症中一個良好的治療標的。

Sepsis is a life-threating condition that arises as a systemic inflammatory response to infection. Due to high circulating cytokine levels increase vascular permeability, septic patients often die of septic shock caused by the hypotension. Despite a high mortality and morbidity, there is no effective and specific drug for sepsis. High mobility group box 1 (HMGB1) is a pro-inflammatory cytokine released in the late stage of sepsis, which is considered as a critical mediator for sepsis pathogenesis. However, inhibition of cytokines couldn’t reduce the mortality of sepsis patients effectively. Previous studies have found that autophagy is involved in lipopolysaccharide (LPS)-induced endothelial hyper-permeability. In addition, autophagy can also regulate the production and secretion of cytokines, such as IL-1 and TNF-α. Moreover, autophagy can modulate phagocytosis in macrophages. In this study, we aim to evaluate the therapeutic potential of inhibiting autophagy against bacterial infection and sepsis-induced inflammatory responses. First, we found that LPS-induced cytokines production of leukocyte was blocked by the inhibition of autophagy. In addition, endothelial hyper-permeability induced by both LPS conditioned medium and HMGB1 were also inhibited in the presence of autophagy inhibitors. Moreover, treatment of autophagy inhibitors enhanced uptake of bacteria by leukocytes. Finally, we demonstrated that blocking autophagy improves the survival rate of septic mice by increasing bacterial clearance and reducing cytokine production and vascular leakage. Taken together, these results suggest that autophagy plays an important role in the sepsis pathogenesis. And autophagy may serve as a potential therapeutic target for septic shock.

Table of Contents
中文摘要	I
Abstract	II
Acknowledgement	III
Table of Contents	IV
List of Figures	VII
Abbreviations Index	VIII
Introduction	1
1. Sepsis	1
1.1. Sepsis : Causes, symptoms and treatments	1
1.2. Pathogenesis of septic shock	2
1.3. Late proinflammatory mediators of sepsis	2
1.4. The difficulty of treatment to sepsis	3
2. Autophagy	4
2.1. Characteristics of autophagy	4
2.2. The role of autophagy in sepsis	6
2.2.1. Vascular leakage and autophagy	6
2.2.2. Cytokine Secretory and autophagy: unconventional secretory pathway	7
2.2.3. Bacterial clearance and autophagy	8
Objective and Specific Aims	10
1. To investigate the roles of autophagy in sepsis-induced endothelial cell hyper-permeability.	10
2. To investigate the roles of autophagy in sepsis-induced cytokine storm.	10
3. To investigate whether the inhibition of autophagy promotes bacterial clearance.	10
4. To evaluate the therapeutic potential of the inhibition of the autophagy in septic mice model.	10
Materials and Methods	12
1. Materials	12
1.1. Cell lines	12
1.2. Recombinant Proteins	12
1.3. Bacteria	12
1.4. Reagents	12
1.5. Antibodies	14
1.6. ELISA kits	14
1.7. Consumables	15
1.8. Instruments	16
1.9. Mice	16
2. Methods	17
2.1. Cell culture	17
2.2. Transwell assay	17
2.3. Isolation of peripheral blood leukocytes	17
2.4. Cytokine measurement	18
2.5. Preparation of E. coli	18
2.6. Phagocytosis assay	19
2.7. Bacterial sepsis models and treatment	19
2.8. Determination of blood and organs bacterial CFU	19
2.9. Vascular leakage in the organs of mice	20
2.10. Vascular leakage in the peritoneal cavity of mice	20
2.11. Statistical analysis	20
Results	21
1. Both HMGB1 and LPS conditioned medium-induced hyper-permeability are blocked by autophagy inhibitors	21
2. Both LPS and HMGB1-induced cytokines production of leukocyte were blocked by the inhibition of autophagy.	22
3. The treatment of autophagy inhibitors promote the bacterial clearance by leukocytes	23
4. Autophagy inhibitors rescue vascular leakage in E. coli-infected BALB/c mice	23
5. Autophagy inhibitors block the cytokine secretion in BALB/c mice infected with E. coli	23
6. Post-treated with autophagy inhibitor enhances bacterial clearance in BALB/c mice infected with E. coli	24
7. Post-treated with autophagy inhibitors improved the survival rate in BALB/c mice infected with E. coli	25
Discussion	26
Conclusion	32
References	33
Figures	43
 
List of Figures
Figure 1. Inhibition of autophagy attenuates LPS and HMGB1-induced hyperpermeability.	43
Figure 2. LPS induces cytokine secretion in human leukocytes.	45
Figure 3. Endothelial hyperpermeability induced by LPS conditioned medium is blocked by autophagy inhibitors.	46
Figure 4. Autophagy inhibitors inhibit LPS and HMGB1-induced cytokine secretion in leukocytes.	47
Figure 5. LPS-induced cytokine secretion is inhibited in LC3 knockdown THP-1 cell.	48
Figure 6. Treatment of autophagy inhibitors enhance phagocytosis of bacteria by leukocytes.	49
Figure 7. Autophagy inhibitors rescue vascular leakage in E. coli-infected BALB/c mice.	50
Figure 8. Cytokine production in E. coli-infected BALB/c mice.	51
Figure 9. Autophagy inhibitors inhibit cytokine secretion in E. coli-infected BALB/c mice.	52
Figure 10. Post-treatment with autophagy inhibitor enhances bacterial clearance in E. coli-infected mice.	53
Figure 11. Post-treatment with autophagy inhibitor improves the survival rate in E. coli-infected BALB/c mice.	54


                                    

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