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研究生: 王麗淑
Wang, Li-Su
論文名稱: 三氧化二砷對THP-1細胞及SVEC4-10細胞之毒性機轉探討
Investigation of Arsenic trioxide cytotoxic mechanisms in THP-1 cells and SVEC4-10 cells
指導教授: 王應然
Wang, Ying-Jan
共同指導教授: 吳明娟
Wu, Ming-Jiuan
學位類別: 博士
Doctor
系所名稱: 醫學院 - 環境醫學研究所
Department of Environmental and Occupational Health
論文出版年: 2014
畢業學年度: 102
語文別: 英文
論文頁數: 97
中文關鍵詞: 硫辛酸第一型血基質加氧酶麩胱甘肽清道夫受體介白素-6血管內皮生長因子
外文關鍵詞: Arsenic, -Lipoic acid, Heme oxygenase-1, Glutathione, Scavenger receptors, IL-6, VEGF
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  • 砷是環境中常見的汙染物質,長期暴露於三氧化二砷中會導致許多主要的免疫細胞,特別是巨噬細胞,改變其生理機能。此論文的第一個部分是探討降低人類前單核細胞THP-1毒性的特性與機制,並且研究硫化還原劑硫辛酸的保護效果。結果顯示,非致死劑量(1M)之三氧化二砷能顯著誘導第一型血基質加氧酶(heme oxygenase-1, HO-1)的表現,但是無法刺激超氧陰離子的產生。當細胞中同時加入HO-1之競爭性抑制劑zinc protoporphyrin (Znpp) 和三氧化二砷時,會加強砷誘導之細胞毒性,此結果表示HO-1具有保護細胞免於砷毒害之作用。低濃度的三氧化二砷(1和2.5 M)可顯著的抑制單核球分化及巨噬細胞標的分子之表達。在THP-1細胞中同時加入硫辛酸和三氧化二砷時,可降低三氧化二砷引起的細胞毒性及HO-1的過度表現,使細胞恢復其氧化還原狀態。此外,硫辛酸可緩解三氧化二砷對THP-1分化的抑制作用,因而增加巨噬細胞之標的分子的表達及清道夫受體的活性。此研究結果顯示,三氧化二砷之細胞毒性與細胞氧化還原狀態失衡有關,硫辛酸可能藉由其還原力、直接螯合砷或是活化細胞的訊息傳遞路徑,而保護細胞。
    研究指出,長期暴露於三氧化二砷會提高心血管疾病之風險。因此,論文的第二個部分主要探討三氧化二砷造成的血管損傷之分子機制。我們以小鼠內皮細胞株SVEC4-10為研究模式,分析三氧化二砷對細胞毒性、基因表現之影響,並進一步探討可能參與的細胞訊息路徑。研究結果顯示,SVEC4-10細胞死亡率與三氧化二砷濃度成正比。添加硫辛酸能完全抑制砷的細胞毒性; 但是,添加tiron雖然能清除ROS,卻無法完全抑制細胞死亡。砷會誘導SVEC4-10細胞的HO-1、介白素-6 (IL-6)、單核細胞趨化因子(MCP-1)及血管內皮生長因子(VEGF)的mRNA表現。添加硫辛酸與三氧化二砷共同培養時,會抑制這些基因之表現,但是tiron則無影響,由此結果推測ROS對於上述基因之表現並不重要。HO-1競爭性抑制劑Znpp的添加劑量與SVEC4-10細胞存活率之間呈倒U字型的相關性,這表示HO-1活性具有低劑量促進生存,高劑量抑制生存的hormesis現象。HO-1 siRNA會抑制砷誘導的VEGF表達。砷也會加強轉錄因子NF-E2-related factor 2 (Nrf2)表現以及NF-κB活化。添加NF-κB 的抑制劑Bay 11-7082會抑制砷所誘導之HO-1及IL-6表達。添加 p38 MAPK的選擇性抑制劑SB203580顯著的抑制了由砷所誘導之HO-1及VEGF之基因表現,而添加JNK的抑制劑SP600125時則會增加 IL-6 表達。此實驗結果表示,當SVEC4-10細胞與砷共同培養時,HO-1的表現是受到Nrf2、NF-κB、p38 MAPK等路徑正向調控,而且HO-1也是VEGF表現的上游調控因子。而IL-6的表現則是受NF-κB及JNKs所調控。總結上述實驗結果,氧化壓力或許與三氧化二砷造成之細胞毒性與內皮細胞基因過度表現有關,但是細胞訊息路徑可能在砷的毒性及基因表現上扮演更重要的角色。

    Inorganic arsenic is a common environmental contaminant; chronic exposure to arsenic can alter the physiology of various key immune cells, particularly macrophages. The aim of first part research is to elucidate the key parameters associated with arsenic-induced toxicity and investigate the potential and mechanism of -lipoic acid (LA), a potent thioreducant, for reducing the toxicity in human promonocytic THP-1 cells. The result shows that a non-lethal concentration of arsenic trioxide (1 M) significantly induced the expression of heme oxygenase-1(HO-1), a response biomarker to arsenic, without stimulating measurable superoxide production. Co-treatment of cells with the HO-1 competitive inhibitor zinc protoporphyrin (Znpp) potentiated arsenic-induced cytotoxicity, indicating that HO-1 confers a cytoprotective effect against arsenic toxicity. In addition, low concentrations of arsenic trioxide (1 and 2.5 M) markedly inhibited monocyte-to-macrophage differentiation and expression of macrophage markers. Treatment of cells with LA attenuated arsenic trioxide-induced cytotoxicity and HO-1 over-expression and restored the redox state. In addition, LA neutralized arsenic trioxide-inhibition of monocyte maturation into macrophages and reversed the expression and activity of scavenger receptors. In conclusion, the cytotoxicity of arsenic trioxide is associated with an imbalance of the cellular redox state, and LA can protect cells from arsenic-induced malfunctions either through its reducing activity, direct interacting with arsenic or stimulating other unidentified signaling pathways.
    Chronic arsenic exposure has been linked to an increase risk in vascular diseases. In second part, we proposed the molecular mechanisms through which arsenic causes injuries to blood vessels, we analyzed the effects of arsenic trioxide on the cytotoxicity, intracellular reactive oxygen species (ROS), the expression of related genes and signaling pathways involved in the SVEC4-10 mouse endothelial cells. Arsenic dose-dependently caused SVEC4-10 cell death, which is completely inhibited by α-lipolic acid (LA), a thioreducant, but partially ameliorated by Tiron, a potent superoxide scavenger. The mRNA levels of heme oxygenase-1 (HO-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) were significantly increased by arsenic. The up-regulation of these can be blocked by LA instead of Tiron, suggesting ROS is not important in their increase. HO-1 competitive inhibitor zinc protoporphyrin improved the cytotoxicty of arsenic in an inverted U dose-response curve, indicating the biphasic hormetic effect of HO-1. HO-1 siRNA decreased VEGF expression in response to arsenic. Arsenic exposure also enhanced NF-E2-related factor 2 (Nrf2) expression, and increased activation of nuclear factor-κB (NF-κB). NF-κB inhibitor Bay 11-7082 reduced arsenic-mediated expression of HO-1 and IL-6. Selective blocking of the MAPK pathways with p38 inhibitor SB203580 significantly decreased arsenic-induced HO-1 and VEGF expression, while JNKs inhibitor SP600125 increased IL-6 expression. These results suggest that in arsenic-treated SVEC4-10 cells, HO-1 expression is mediated through Nrf2-, NF-κB- and p38 MAPK-dependent signaling pathways, and serves as an upstream regulator of VEGF. IL-6 expression is regulated by NF-κB and JNKs. In conclusion, oxidative stress may be associated with arsenic-induced cytotoxicity and endothelial gene up-regulation, but signaling transduction dominates the direct effects of ROS.

    中文摘要 I Abstract III 誌謝 V Contents VI Table List X Figure List XI Abbreviations XIII Publication list XV Introduction XVI Chapter 1 1 1.1 Materials and methods 2 1.1.1 Chemicals 2 1.1.2 Cell culture 2 1.1.3 Cell viability analysis 2 1.1.4 mRNA expression of HO-1, CD36 and SR-A 3 1.1.5 Immunoblotting of HO-1 expression 3 1.1.6 Measurement of superoxide by flow cytometry 4 1.1.7 Measurement of glutathione (GSH) by flow cytometry 4 1.1.8 Preparation of LDL and DiI-acLDL (acetylated LDL labeled with 1,1’-dioctadecyl-3,3,3’,3’-tetramethylindo-carbocyanine perchlorate) 4 1.1.9 Measurement of scavenger receptor activity during macrophagic differentiation 5 1.1.10 Statistical analysis 5 1.2 Results 6 1.2.1 As2O3 causes cytotoxicity and HO-1 over-expression in THP-1 monocytes 6 1.2.2 As2O3 induces oxidative stress in THP-1 monocytes 7 1.2.3 LA attenuates As2O3-induced cellular malfunctions in THP-1 monocytes 7 1.2.4 LA neutralizes As2O3-reduced monocyte-to-macrophage differentiation 8 1.2.5 LA reduced As2O3-induced cytotoxicity, redox state and HO-1 overexpression in THP-1 macrophages 10 1.3 Discussion 12 1.4 Tables and figures 17 Chapter 2 27 2.1 Materials and Methods 28 2.1.1 Chemicals 28 2.1.2 Cell culture 28 2.1.3 Cell viability analysis 28 2.1.4 Intracellular ROS analysis 29 2.1.5 Reverse transcription quantitative PCR (RT-Q-PCR) analysis of heme oxygenase-1 (HO-1), interleukine-6 (IL-6), monocyte chemoattractant protein (MCP-1), vascular endothelial growth factor (VEGF), and nuclear factor E2-related factor 2 (Nrf2) 29 2.1.6 Western blot analysis 29 2.1.7 SiRNA knockdown of HO-1 30 2.1.8 Statistical Analysis 31 2.2 Results 32 2.2.1 Cytotoxicity of arsenic can be reduced by -lipoic acid and Tiron 32 2.2.2 Effects of -lipoic acid (LA) and Tiron on arsenic trioxide-mediated ROS generation 33 2.2.3 ROS alone is insufficient for arsenic trioxide-induced heme oxygenase-1 (HO-1) expression 33 2.2.4 Hormetic effect of arsenic-induced HO-1 expression 34 2.2.5 ROS is not sufficient for arsenic trioxide-mediated expressions of interleukine-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) 34 2.3.6 Arsenic trioxide-upregulated VEGF expression is HO-1 dependent 35 2.2.7 Arsenic trioxide affects nuclear factor E2-related factor 2 (Nrf2) expression and nuclear factor-κB (NF-B) activation 36 2.2.8 Effect of arsenic on MAPK signaling pathways 38 2.2.9 Effect of signaling inhibitors on arsenic-mediated HO-1, Nrf2, IL-6 and VEGF induction 39 2.3 Discussion 41 2.4 Tables and figures 48 References 60

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