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研究生:賴佩芳
研究生(外文):Pei-Fang Lai
論文名稱:活化轉錄因子3(ATF3)透過調控高遷移率族蛋白B1 (HMGB1)影響敗血症之預後
論文名稱(外文):Activiting Transcription Factor 3 Affects the Prognosis of Sepsis through Regulating HMBG1
指導教授:陳松鶴
指導教授(外文):Sung-Ho Chen
口試委員:鄭敬楓邱鐵雄林 恆黃彥達
口試委員(外文):Ching-Feng ChengTed H. ChiuHeng LinYen Ta Huang
口試日期:2013-07-08
學位類別:博士
校院名稱:慈濟大學
系所名稱:藥理暨毒理學碩士班/博士班
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:2013
畢業學年度:101
語文別:英文
論文頁數:96
中文關鍵詞:敗血症Toll-Like 受體4內毒素活化轉錄因子3高遷移率族蛋白B1
外文關鍵詞:sepsisTLR 4endotoxinATF 3HMGB1
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背景及目的
照顧嚴重敗血症的病患醫護人員必須面對疾病上的種種風險,例如極高的致死率和影響生活品質的各種併發症,社會也需要付出龐大的資金及資源。然而到目前為止敗血症的致病機轉仍未完全了解,既使已經發展出許多的治療策略,敗血症的死亡率仍然相當高。Toll-Like 受體4 (Toll-Like Receptor 4, TLR 4) 的訊息傳導路徑是目前已知的敗血症重要致病路徑,細菌內毒素 (Lipopolysaccharide, LPS) 主要透過Toll-Like 受體4誘發先天性的免疫反應去對抗內毒素血症,能夠當作誘發動物敗血症的工具。活化轉錄因子3(ATF 3)已被證實是Toll-Like 受體4 的訊息傳導路徑的負向調節者。高遷移率族蛋白B1(HMGB1)則在敗血症的較後期具有重要角色。然而活化轉錄因子3和高遷移率族蛋白B1分別在敗血症的免疫反應中如何運作尚未充分瞭解,更不清楚彼此之間相互的關係。因此我們試著去釐清活化轉錄因子3、高遷移率族蛋白B1及Toll-Like 受體4 的訊息傳導路徑在動物內毒素血症上如何影響預後,期望藉此對於人類敗血症有更進一步的理解,以便挽救更多的生命和維護生活品質。
方法及材料
八到十週大的小鼠,包含C57BL/6 野生型小鼠及活化轉錄因子3基因剃除鼠,分別有施打生理食鹽水及內毒素的組別,還有另一組基因剃除鼠使用重組腺病毒相關病毒載體(recombinant adeno-associated virus; AAV)先感染帶有ATF3基因的病毒,活化轉錄因子3在鼠體內表現出來後再施打內毒素。施打內毒素後不同的時間點犧牲老鼠以取得血液及器官樣本。死亡率則是記錄24小時的結果。所取得的血液及器官樣本可進行酵素免疫分析法(Enzyme-linked immunosorbent assay,簡稱ELISA),西方墨點式法(Western blot)及聚合酶連鎖反應(Polymerase Chain Reaction, PCR)去分析許多不同發炎介子在不同時間的表達,器官樣本另以蠟塊切片進行染色,觀察器官受損及發炎介子浸潤的情形。培養巨噬細胞以內毒素處理,或先行以小干擾RNA(Small interfering RNA, siRNA)將活化轉錄因子3基因表現抑制後內毒素處理,再分析其培養液及細胞在發炎相關因子上的表現。
實驗結果
我們研究發現得到敗血症的病患比其他疾病的患者血清中的高遷移率族蛋白B1高出十倍之多。我們也證實了將老鼠活化轉錄因子3的基因剃除再受到內毒素的攻擊後,將會有較高的致死率及器官受損程度,血清及肺的組織中含有較高的第六間白素(Interleukin-6, 簡稱IL-6)、腫瘤壞死因子-α (tumor necrosis factor-α, TNF-α)、一氧化氮(Nitrogen monoxide, NO)、第一型單核球細胞趨化蛋白(Monocyte Chemoattractant Protein-1, MCP-1) 和高遷移率族蛋白B1(HMGB1)這些發炎介子的表現。在in vitro 的實驗中用小干擾RNA (siRNA) 去阻斷巨噬細胞中活化轉錄因子3的基因表現再施以內毒素,會發現發炎介子的表現雷同於被內毒素傷害的基因剃除鼠。若是以帶有活化轉錄因子3的基因的重組腺病毒相關病毒感染基因剃除鼠,以恢復小鼠的基因表達,會發現可降低小鼠施打內毒素後的死亡率及器官受損程度,並且高遷移率族蛋白B1上升的情形也會較為緩和。
結論
活化轉錄因子3可以保護被內毒素攻擊的小鼠免於死亡及多重器官衰竭,例如肺及肝損傷。內毒素攻擊時的小鼠體內增加了活化轉錄因子3可避免過多的發炎介子形成及減少高遷移率族蛋白B1釋放出來造成器官的傷害,甚至於死亡。本研究不但增加了對敗血症機轉的認識,活化轉錄因子3或可成為新的敗血症治療策略。

Background and purposes
Caring for patients with severe sepsis is costly and must confront great risk. Because the complete mechanism of severe sepsis is still vague, and the mortality rate of sepsis is very high even various treatment strategies were developed. Lipopolysaccharide (LPS) triggers innate immunity mainly via TLR 4 signaling causing sepsis, thus LPS induced sepsis can be used as an animal model. ATF 3 is a negative regulator of TLR 4 signaling. HMGB1 plays a critical role in the final step of sepsis. However, the mechanisms of ATF 3 and the role of HMGB1 in regulating innate immunity-induced sepsis are incompletely understood. We try to clarify the role of ATF3 and HMGB1 in endotoxemic TLR4 pathway to advance the understanding of human sepsis.
Methods and materials
Eight to ten-week-old male B6 mice and ATF3 knockout mice were divided randomly into several groups. Control groups were administered with saline, and experimental groups were administered with 5 mg/kg of LPS intraperitoneally (i.p.) at different time points to induce endotoxemia. Another ATF3 knockout mice were pretreated with AAV-ATF3 to replenish ATF3 expression before LPS treatment. Blood sample and organs were collected at 0,3,6,12,24 hours post-treatment. Mortality rate was calculated at 24 hours. Blood samples (0.5 ml) were centrifuged and frozen at -80°C for subsequent assay. The liver and lung tissues were embedded in paraffin and studied using immunofluorescence and immunoblotting of cytosolic inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB), HMGB1 and ATF3 proteins. RAW264.7 cells (a mouse macrophage cell line) were treated with LPS (200 ng/ml), 24 hours later culture median and cells were harvested for further assay.
Results
We found that serum HMGB1 levels were 10-fold higher in patients with sepsis than normal controls. We further demonstrated that ATF 3 gene knockout in mice subjected to LPS-induced endotoxemia correlates with an increase in the mortality rate and the elevated expression of IL-6, TNF-α, NO, MCP-1 and HMGB1 in the lung tissues or serum. The biochemical effects of ATF3 were observed in in vitro macrophages, and blocked by ATF3 siRNA treatment. We have also shown that adeno-associated virus mediated ATF3 gene transfer protected ATF3 knockout mice from LPS-induced mortality and lung injury. In addition, ATF3 knock down increased LPS-induced release of HMGB1with aggravation of the tissue injury on sepsis.
Conclusion
In conclusion, the existence of ATF3 can offer protection against mortality and organs dysfunction in endotoxemia. Upregulation of ATF3 not only contributes to the reduced release of inflammatory molecules, especially HMGB1 which induced lung injury, but also increased the survival rate of mice after LPS challenge. Therefore, suppressing LPS-induced inflammation with ATF3 induction or ATF3 mimetics may be an important strategy for sepsis therapy.

Chinese abstract………………………………………………………………….I
English abstract…………………………………………………..…………....IV
Chapter 1. General introduction…………………………………………….…..1
1.1 Sepsis definition, epidemiology……………………………………...……1
1.2 Insights into the pathogenesis of sepsis……………………..……………2
1.2.1. Systemic inflammatory response syndrome (SIRS) vs. compensatory anti-inflammatory response syndrome (CARS)…………………..…..3
1.2.2. Pattern-recognition receptors (PRRs): Toll-like receptors (TLRs)…4
1.2.3 Inflammatory mediators during sepsis……………………………....7
1.3 ATF3………………………………………………….……………………8
1.4 HMGB1……………………………………………………………...……10
1.5. Animal models of experimental sepsis…………………………….…….12
1.5.1 Endotoxaemia……………………………………………………….13
1.5.1.1 LPS………………………………………………………..…….13
1.5.2 Bacteremia……………………………………………………..……14
1.5.3Caecal ligation and puncture………………………………………..14
1.6 A brief sum-up………………………………………………….………..15

Chapter 2. Material and methods…………………………………………….…..16
2.1 Animal source………………………………………………………………16
2.2 Experimental procedures……………………………………..……………16
2.3 Culture of RAW 264.7 macrophage cell line…………………………..…..17
2.4 Plasma TNF-α, IL-6and HMGB1measurement……………………....17
2.5 IL-6 and TNF-α mRNA measurement…………………………………….18
2.6 Plasma and medium NO measurement……………………………...…….19
2.7 Immunofluorescence (IF)…………………………………………….……19
2.8 Isolation of nuclear and cytosolic HMGB1 and NF-κB proteins………...20
2.9 Western blotting…………………………………………………………….21
2.10 Histopathology………………………………………………………...…..22
2.11 Lung injury assessment………………………………………………..….23
2.12 Measurement of the survival rate in mice………………………………..23
2.13 Adeno-associated virus preparation and gene transfer…………….……24
2.14 Statistical analysis……………………………………………………,…..24

Chapter3. ATF3 protects against LPS-induced lung injury in mice via inhibiting HMGB1 expression
3.1 Introduction…………………………………………………………...……25
3.2 Experimental design……………………………………………………..…27
3.2.1 In vivo……………………………………………………………….…27
3.2.2 In vitro…………………………………………………………………28
3.3 Result……………………………………………………………….………29
3.3.1 The expression of ATF3 may protect mice from LPS-induced endotoxemic mortality ……………………………………………..…….…..29
3.3.2 ATF3 expression was up-regulated in mice after LPS treatment …….30
3.3.3 ATF3 deficiency increased inflammation-induced lung injury in endotoxemic mice ………………………………………………………....…30
3.3.4 ATF3 knockout increased MCP-1 in inflammation-induced lung injury in mice induced by LPS …………………….……………………………….31
3.3.5 ATF3 knockout increased inflammation mediators in endotoxemia mice through NF-κB pathway …………………………………………………....31
3.3.6 Patients with sepsis syndrome had elevated serum HMGB1 levels ………………………………………………………….……33
3.3.7 ATF3 modulated HMGB1 release in LPS-induced endotoxemia in mice ……………………………………………...…………………..34
3.4 Discussion ………………………………………………………………….36
3.5 conclusions ……………..………………………………………………….42


Chapter 4 ATF3 protects against LPS-induced acute liver inflammation and reduces fatality in mice
4.1 Introduction ……………………………………………….……………….43
4.2 Experimental design …………………………...…………………………..46
4.3 Result ……………………………………………………………………….47
4.3.1 Changes in physiological parameter upon LPS challenge in mice .....47
4.3.2 ATF3 prevents LPS-induced endotoxemic liver injury ………………47
4.3.3 ATF3 improves the survival rate of LPS-induced endotoxemic mice ………………………………………………………………….48
4.4 Discussion ……………………….…………………………………………49
4.5 conclusions …………………………………….…………………………..52

Chapter 5 General conclusion ……………………………………………...……53

Chapter 6 figures and tables
Figure contents pages
Figure 1 survival rate of WT (wild type) and KO (ATF3 knockout) mice…………54
Figure 2 Re-introduction of ATF3 by adeno-associated virus………………...…. 55
Figure 3 Expression level of ATF3 in the lung tissues of WT (wild type) and KO (ATF3 knockout) mice challenged with LPS………………………...... 57
Figure 4 ATF3 inhibited polymorphonuclear leukocyte infiltration and lung injury in mice after LPS treatment………………………………………..….. 59
Figure 5 ATF3 knockout increased LPS-induced MCP-1 level in the lung tissues of mice…………………………………………………………….. ..…... 61
Figure 6 Effects of ATF3 knockout on LPS-induced translocation of NF-KB p65 in mice and macrophages………………………………………………….62
Figure 7 Effects of ATF3 knockout on LPS-induced expression of IL-6, TNF- and iNOS……………………………………………………………..…….. 64
Figure 8 Serum HMGB1 levels in septic patients………………………………...66
Figure 9 ATF3 knockout enhanced LPS-induced increased in serum and cytosolic HMGB1 concentrations in mice………………………………………..67
Figure 10 ATF3 siRNA enhanced LPS-induced elevation of ATF3 and cytosolic HMGB1 expression, and medium HMGB1 and nitrite concentrations in macrophage culture……………………………………………………..69
Figure 11 Re-introduction of ATF3 by adeno-associated virus attenuated lung injury, and reduced serum nitrite and HBGB1 concentrations in ATF3 KO mice following LPS treatment…………………………………………….….71
Figure 12 Change of physiological parameter of white blood cells (WBC) in whole blood at different hours in different groups of mice………………….…73
Figure 13 Representative sections of liver tissues in mice model of endotoxemia.74
Figure 14 ATF3 increases mice survival rate in LPS-induced endotoxemia……...75
Figure 15 A schematic diagram depicting that ATF 3 protects endotoxemia….….76

Table Contents pages
Table 1 Diagnostic criteria for sepsis……………………………………….…….77
Table 2 Severe Sepsis……………………………………………………………..78
Table 3 Primers used………………………………………………………………79
Table 4 Patient demographics for sepsis (–) and sepsis (+) patients………………80

Chapter 6 References …………………………………………………………..…81

Appendix
Appendix 1: published manuscript 1
Appendix 2: published manuscript 2

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