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系統識別號 U0026-2307201517084000
論文名稱(中文) 自體吞噬作用在環境毒物誘發之皮膚炎與毒性反應中所扮演之角色
論文名稱(英文) The role of autophagy in environmental toxicants-induced dermatitis and toxicity
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 103
學期 2
出版年 104
研究生(中文) 李宥萱
研究生(英文) Yu-Hsuan Lee
學號 S78991019
學位類別 博士
語文別 英文
論文頁數 99頁
口試委員 指導教授-王應然
召集委員-何元順
口試委員-潘敏雄
口試委員-王伯智
口試委員-郭靜娟
口試委員-黃步敏
口試委員-黃東裕
中文關鍵字 自體吞噬  六價鉻  TNF-α 與 IL-1α  過敏性接觸性皮膚炎  奈米銀  活性氧物種 
英文關鍵字 autophagy  hexavalent chromium  TNF-α and IL-1α  hypersensitivity  silver nanoparticles  ROS 
學科別分類
中文摘要 自體吞噬作用(autophagy)為多種生物體面對環境壓力時的防禦機制,此機轉能調節許多生理機能,並且在調控細胞存活、死亡或者發炎反應的過程中佔有舉足輕重的作用能力。許多的研究證據指出,環境毒物像是重金屬與奈米粒子會誘發自體吞噬作用與細胞的損傷,而這些反應的產生亦證實環境所造成生物體在分子機轉上的改變與許多疾病的發生是有關連性的。鉻所誘發之過敏性接觸性皮膚炎在職業性皮膚疾病當中是很常見的案例。六價鉻(Cr (VI))會經由活性氧物種(reactive oxygen species, ROS)活化Akt、NF-κB與MAPK等訊息傳遞路徑,並且引起細胞的死亡。ROS除了會造成鉻所誘發之過敏性接觸性皮膚炎之外,過量的ROS會引起氧化壓力並且造成奈米粒子之毒性反應。近期有許多研究報告指出重金屬與奈米物質皆能誘發自體吞噬作用的產生,但透過自體吞噬所調控過敏性接觸性皮膚炎與奈米毒性之反應機制仍不清楚。而本篇研究主要在了解六價鉻導致皮膚過敏致病的分子機轉中,其ROS與自體吞噬作用間的關係,此外本研究亦選用在生活上已被廣泛應用且可能具有生物毒性之不同粒徑奈米銀(AgNPs)進行細胞(NIH 3T3 cells)毒性試驗,以了解奈米銀可能造成的生物效應指標與毒性機轉。首先,在不同濃度的六價鉻處理之下,皆會誘導ROS、細胞凋亡與自體吞噬作用的產生,然而加入N-乙醯基半胱胺酸之後會抑制細胞凋亡與自體吞噬的產生因而影響細胞存活率。六價鉻會藉由活化Akt、NF-κB與MAPK等訊息傳遞路徑而導致細胞激素IL-1α與TNF-α的分泌量增加,而不意外的這些受到刺激而增加活性與分泌的現象,不論在體外還是體內的研究中皆能被N-乙醯基半胱胺酸所抑制,此結果證實N-乙醯基半胱胺酸可以透過抑制ROS的生成進而降低細胞死亡與細胞激素的分泌,因此減緩了鉻所誘發的過敏性接觸性皮膚炎。針對奈米粒子的實驗結果,奈米銀會被NIH 3T3 細胞攝入,並且聚集於核內體(endosome),較小粒徑的奈米銀粒子(SAS)具有較高的毒性,本研究的結果顯示SAS會導致較多的溶酶體(lysosome)變形腫脹、自體吞噬作用停滯與細胞死亡,而奈米銀所誘導的細胞自體吞噬機轉可能是藉由增加氧化壓力與內質網壓力(ER stress)所造成的,奈米銀的暴露會增加內質網壓力蛋白(IRE1)與自體吞噬蛋白 (LC3-II)的表現,然而p62蛋白的累積則指出自體吞噬作用受到抑制,因此細胞啟動自體吞噬的反應,可能是對抗奈米粒子誘發細胞毒性的重要調控因子,亦可作為奈米重要的生物毒性指標之一。上述的研究成果說明了自體吞噬作用對於生物系統的影響,並且證明了自體吞噬機轉為引發過敏性皮膚炎與發展新的毒性研究試驗方法中相當重要的一環。
英文摘要 Autophagy serves as a defense strategy when facing environmental stress in several organisms. This conserved physiological process plays a pivotal role in the regulation of homeostasis and also cell survival/death and inflammatory responses. The increasing evidence that various environmental toxicants, such as heavy metals and nanoparticles (NPs), lead to autophagy and cellular damage suggests that the influence of the environment on an organism at the molecular level represent a key variable in several diseases. Chromium hypersensitivity (chromium-induced allergic contact dermatitis) is an important issue in occupational skin disease. Hexavalent chromium (Cr (VI)) can activate the Akt, NF-κB, and MAPK pathways and induce cell death, via the effects of reactive oxygen species (ROS). In addition to causing chromium hypersensitivity, high ROS levels are indicative of oxidative stress and also contributed to NPs toxicity. More and more studies have recently reported that heavy metals and nanomaterials can induce autophagy but the mechanisms by which autophagy regulates hypersensitivity and nanotoxicity remains unclear. In the present study, we investigated : (1) The relationship among ROS, autophagy and Cr(VI)-induced hypersensitivity and (2) the nanoparticle toxicity bio-indicators and possible mechanisms of different size silver nanoparticles (AgNPs)-induced cytotoxicity in the NIH3T3 cell line. First of all, the induction of apoptosis, autophagy, and ROS were observed after different concentrations of Cr(VI) treatment. HaCaT cells pretreated with NAC exhibited a decrease in apoptosis and autophagy, which could affect cell viability. In addition, Cr(VI) activated the Akt, NF-κB and MAPK pathways and thereby increasing IL-1α and TNF-α production. All of these stimulation phenomena were inhibited by NAC in both in vitro and in vivo studies. These novel findings indicate that NAC may prevent the development of chromium hypersensitivity by inhibiting ROS-induced cell death and cytokine expression. Secondary, AgNPs were taken up by NIH 3T3 cells and localized within the intracellular endosomal compartments. Smaller AgNPs (SAS) were more toxic than larger AgNPs (LAS). Our results suggest that SAS leads to more lysosomal swelling, arrested autophagic flux and cell death. The mechanisms underlying the AgNPs-induced autophagy in cells could be mediated by the activation of oxidative stress and endoplasmic reticulum (ER) stress signaling pathways. AgNPs treatment can trigger the expression of ER stress and autophagy markers (IRE1and LC3-II). However, the autophagy substrate, p62, accumulated in AgNPs-treated cells indicating that the autophagy process was inhibited. Thus, autophagy activation may be a key player in the cellular response against nano-toxicity. Taken together, these works illustrate the influence of autophagy on biological systems and demonstrate the study of autophagy is pivotal in the development of hypersensitivity and new approaches for toxicological studies.
論文目次 中文摘要 I
Abstract III
致謝 V
Tables List VIII
Figures List IX
Abbreviations XI
Publication list XII
Introduction 1
1. Environmental toxicants 1
2. Cr(VI)-induced contact dermatitis 2
3. AgNPs cellular uptake and toxicity 3
4. Autophagy as a stress defense mechanism 4
5. Apoptosis, cytotoxicity and skin disease 5
Objectives 7
Materials and Methods 8
1. Preparation and characterization of AgNPs 8
2. Cell culture and treatment 10
3. Cell viability assay 11
4. Cell morphology by phase-contrast microscopy and electron microscopy 12
5. Investigation of different mechanisms of endocytic AgNPs uptake 12
6. Intracellular reactive oxygen species (ROS), glutathione (GSH) or ER stress measurement 13
7. Detection and quantification of acidic vesicular organelles with acridine orange staining 15
8. Confocal imaging and evaluation of the LC3 and LAMP-1proteins 15
9. Detection of apoptosis using Annexin V/ PI and DAPI staining 16
10. Western blot analysis 17
11. mRNA expression of TNF-α and IL-1α 17
12. ELISA for IL-1α detection 18
13. Immunohistochemical (IHC) staining analysis 19
14. Administration of NAC and treatment of Cr(VI) injected albino GP 19
15. Statistical analysis 20
Results 21
Part 1. N-acetylcysteine attenuates hexavalent chromium-induced hypersensitivity through inhibition of cell death, ROS-related signaling and cytokine expression. 21
1.1 Protective effect of NAC on cell viability 22
1.2 NAC attenuated Cr(VI)-induced apoptotic cell death 22
1.3 Effect of NAC on Cr(VI)-induced autophagy in HaCaT cells 22
1.4 Cr(VI) treatment induced hydrogen peroxide/ROS generation in HaCaT cells, which were attenuated by NAC 23
1.5 Effect of NAC on Cr(VI)-stimulated activation of the Akt, NF-κB and MAPK pathways 23
1.6 NAC inhibited the expression of IL-1α and TNF-α mRNA induced by Cr(VI) in HaCaT cells 24
1.7 NAC administration decreased the activation of the Akt, NF-κB, MAPK pathway and the expression of cytokines in albino guinea pig 25
Part 2. Cytotoxicity, oxidative stress, apoptosis and the autophagic effects of silver nanoparticles in mouse embryonic fibroblasts. 26
2.1. AgNPs physical-chemical characterization and dispersion in water or cell culture media 27
2.2. Cellular uptake of silver nanoparticles 27
2.3. Effects of AgNPs on cellular morphology and cytotoxicity 28
2.4. Effects of AgNPs on cellular reactive oxygen species (ROS), glutathione (GSH) and the expression of Heme oxygenase 1 (HO-1) 29
2.5. AgNPs induced morphological and biochemical markers of autophagy in NIH 3T3 cells 30
2.6. Measurements of apoptosis in NIH 3T3 cells treated with AgNPs 31
Part 3. Endoplasmic reticulum stress-triggered autophagy and lysosomal dysfunction contribute to the cytotoxicity of amine-modified silver nanoparticles in NIH 3T3 cells. 32
3.1. Physical-chemical characterization of amine-modified AgNPs 33
3.2. Effect of SAS and LAS on cellular viability and uptake 34
3.3. Effects of AgNPs on cellular reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress 35
3.4. AgNPs induce ultrastructural alterations 37
3.5. AgNPs induced biochemical markers of autophagy and lysosome in NIH 3T3 cells 37
3.6. Measurements of apoptosis in NIH 3T3 cells treated with AgNPs 39
Discussion 41
Conclusion 49
Reference 50
Appendix 91

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