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研究生:張紘綸
研究生(外文):Hong-Lun Tiunn
論文名稱:奈米氧化鋅微粒呼吸暴露對小鼠肺部過敏性氣道發炎反應之探討
論文名稱(外文):Inhalation Exposure to Zinc Oxide Nanoparticle Induced Allergic Airway Inflammation in Mice
指導教授:鄭尊仁鄭尊仁引用關係
指導教授(外文):Tsun-Jen Cheng
口試委員:林嬪嬪吳焜裕蕭大智
口試委員(外文):Pin-Pin LinKuen-Yuh WuTa-Chih Hsiao
口試日期:2015-07-27
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文出版年:2015
畢業學年度:104
語文別:英文
論文頁數:72
中文關鍵詞:氧化鋅奈米微粒肺部毒性嗜酸性球
外文關鍵詞:zinc oxide nanoparticleeosinophilallergic airway inflammation
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前言
奈米氧化鋅(ZnO NPs)因其物化特性被大量使用在許多產品中,例如:防曬乳、化妝品、半導體與太陽能電池。龐大的需求帶動ZnO NPs的大量生產,但ZnO NPs製造廠工作者職業暴露可能造成的危害仍未被完整討論。早先的研究發現,小鼠以口咽暴露的方式暴露ZnO NPs會誘發過敏性氣道發炎反應。且已有研究指出ZnO NPs和低劑量之致敏原共同暴露時,會產生佐劑效應,使過敏反應增強。在法律管制上,臺灣職安署截至本研究完成時,僅制定鋅金屬燻煙之可容許暴露劑量(PEL)為5 mg/m3,並未制訂ZnO NPs之管制標準。本研究使用低於現行鋅金屬燻煙PEL之ZnO NPs對小鼠進行全身性呼吸暴露,以探討在自然暴露情境下ZnO NPs是否能引發之過敏性氣道發炎反應(AAI)與和致敏原共同暴露時是否能產生佐劑效應。
方法
本研究使用七週大的雌性C57BL/6J小鼠,並使用奈米微粒產生器製備ZnO NPs。動物置於全身暴露腔中進行暴露。本研究分成兩部分,AAI部分,動物隨機分成兩組:實驗組暴露2.5 mg/m3的ZnO NPs,一天五小時,連續五天;控制組則暴露過濾空氣。暴露結束後第一、三、七天進行犧牲。佐劑效應實驗部分則將動物分為四組,分別暴露:過濾空氣、雞卵蛋白(OVA)、ZnO NPs或OVA+ZnO NPs。並在暴露結束後的第一天犧牲。肺泡灌洗液將會蒐集並進行免疫細胞數量計數、細胞形態分析、生化指標及細胞激素之測量。左肺則進行H&E染色用以觀察肺部組織病理變化。
結果
在AAI實驗中,ZnO NPs粒徑幾何平均數為60.6奈米,重量濃度為2.5 mg/m3。而在佐劑效應實驗中,ZnO NPs粒徑幾何平均數與重量濃度分別為61.1奈米、1.5 mg/m3。AAI實驗在暴露後第一天與第三天觀察到肺泡灌洗液中總細胞數及嗜中性球數目顯著的增多,且在三個犧牲時間點均觀察到嗜酸性球的出現。同時在暴露後的一天觀察到細胞激素IL-5, IL-13, TNF-α, IFN-γ顯著上升。在佐劑效應實驗部分,ZnO NPs組和OVA+ZnO NPs共同暴露組均觀察到肺泡灌洗液中總細胞數、嗜中性球數顯著的上升,但沒有觀察到嗜酸性球的出現。在細胞激素的部分,ZnO NPs組與OVA+ZnO NPs組在IL-5、 IL13、TNF-α、IFN-γ四種細胞激素的濃度有顯著的上升。AAI實驗與佐劑實驗之血清中IgE抗體均低於偵測下限。
討論
在AAI的部分,2.5 mg/m3 ZnO NPs暴露造成嗜酸性球的出現與IL-5的上升,這指出暴露造成過敏性氣道反應,且此反應的機轉與Th2細胞相關聯。相反的,在佐劑效應實驗的ZnO NPs暴露組中並未發現嗜酸性球增多的反應,但有觀察到IL-5的上升。顯示1.5 mg/m3 ZnO NPs所造成的AAI反應並未產生可觀察的嗜酸性球聚集現象,但與AAI相關的細胞激素仍觀察到上升的現象。
佐劑效應的部分,單獨暴露40μg OVA組在各項發炎與AAI的指標上均未有顯著的上升。而OVA+ZnO NPs組則觀察到在各項指標有顯著的上升。同時,與AAI關聯之細胞激素有顯著的上升。ZnO NPs組與共同暴露組有相似的結果。將ZnO NPs組與OVA+ZnO NPs組相比較後,雖然在各樣指標上前者均高於後者,但並沒有觀察到兩組間有顯著差異。基於前述的觀察,本研究無法判定ZnO NPs與OVA共同暴露時,是否有佐劑效應並提升OVA的效果。
為了與先前的研究進行比較,本研究使用多路徑微粒沉積模式嘗試將暴露腔的環境濃度轉換成動物肺部暴露到的劑量。經換算後,本研究使用在AAI實驗的暴露濃度為0.507 mg/kg。在與其他研究比較後發現,即便總暴露劑量相近,但暴露劑量率越高所造成的過敏性氣道發炎反應越明顯。
結論
本研究所用暴露濃度遠低於職業暴露恕限值,但在小鼠肺泡中仍可觀察到顯著發炎與免疫反應,顯示現行之恕限值可能無法作為ZnO NPs之防護標準。另一方面,結果顯示ZnO NPs可能引發過敏反應,值得進一步探討其機制。

關鍵字: 氧化鋅, 奈米微粒, 肺部毒性, 嗜酸性球

Introduction
Zinc oxide nanoparticles (ZnO NPs) have been widely utilized in cosmetics, sunscreens, semiconductors, and solar panels. Previous research found mice had developed an allergic airway inflammation (AAI) after ZnO NPs exposure via oropharyngeal aspiration and an allergic adjuvant effect had be detected when ZnO NPs co-exposed to an allergen. Current permissible exposure level (PEL) of zinc fume set by TWOSHA is 5 mg/m3, but there was no PEL specific for ZnO NPs. In the present study, we focused on two effects caused by ZnO NPs: the first is the AAI; and the second is the allergic adjuvant effect. In order to explore the relationship between inhaled ZnO NPs exposure and AAI, we used half of the PEL of zinc fume as exposure dose. In the allergic adjuvant effect experiment, we used 30% of PEL of zinc fume as exposure dose and OVA as an allergen to reveal the possible allergic adjuvant effect caused by ZnO NPs.
Method
7-weeks old female C57BL/6J mice were used in this study. ZnO NPs which used in this study was made by nanoparticle generator. The study contained two parts, the AAI experiment and the adjuvant experiment. In AAI experiment, animals were randomly divided into two groups: the ZnO NPs group and the control group. Animals were sacrificed at day 1, day 3 and 1 week after exposure. In the adjuvant experiment, animals were randomly separated into four groups: ZnO NPs, OVA, ZnO NPs+OVA and control. Animals were sacrificed at day 1 after exposure. Bronchoalveolar lavage fluid (BALF) was collected for total cell count, cell differential count, biomarkers and cytokines measurement.
Result
Diameter of ZnO NPs was 60.6 nm in AAI experiment and 61.1 nm in adjuvant experiment. Diameter of ZnO NPs between two experiments did not show significant difference. Mass concentration measured by filter weighting was 2.5 mg/m3 in AAI experiment and 1.5 mg/m3 in adjuvant experiment.
In AAI experiment, total cell count significantly increased at day 1, and slightly increased at day 3 and 1 week after exposure. Neutrophil count shared same trend with total cell count. Eosinophil count increased in all time points, but decreased rapidly at day 3 and 1 week after exposure. IL-5, IL-13, TNF-α and IFN-γ significantly increased at day 1 after exposure.
In adjuvant experiment, total cell count significantly increased in OVA+ZnO NPs group and ZnO NPs group, but there was not significantly different between two groups. Eosinophil was not detected in any exposure group. Results of Cytokine levels of ZnO NPs group shown that IL-5, IL-13, TNF-α and IFN-γ significantly increased.
Discussion
In AAI experiment, observation of eosinophil recruitments and IL-5 increase confirmed 2.5 mg/m3 ZnO NPs exposure caused AAI. Also, the rapid decrease of eosinophil count indicated AAI recovered after exposure source was removed.
In adjuvant experiment, eosinophil was not detected in the ZnO NPs group or the OVA+ZnO NPs group, but the level of IL-5 increased in both two groups. These indicated 1.5 mg/m3 of ZnO NPs failed to recruit eosinophils in BALF, but it still triggered an AAI-related pathway and increased level of cytokines.
Conclusion
Inhaled ZnO NPs exposure induced AAI even in relatively low doses compared to PEL of zinc fume. Up to date, there is still no regulation for nanomaterial in occupational health. PEL of ZnO NPs is necessary to set up in order to protect workers’ health. Moreover, the dose-response relation and the mechanism of ZnO NPs-induced AAI are not fully revealed by the scientific society yet. Further research will be essential to reveal these problems.

Keywords: Zinc oxide nanoparticle, eosinophil, allergic airway inflammation

Contents
誌謝 i
摘要 ii
Abstract iv
Contents vii
List of Figures x
List of Tables xii
Chapter 1. Introduction 1
1.1 Background 1
1.2 Objectives 3
1.3 Experimental approaches 4
Chapter 2. Literature Review 5
2.1 Toxicity of Zinc oxide nanoparticle 5
2.2 Allergic airway inflammation 6
2.3 Allergic adjuvant effect of ZnO NPs 8
2.4 Inhalation exposure study of ZnO NPs 9
2.5 Previous studies of ZnO NPs by our team 10
Chapter 3. Material and Method 11
3.1 Animal 11
3.2 ZnO NPs generation and characterization 11
3.2.1 ZnO NPs generation system 11
3.2.2 The whole body exposure chambers 12
3.2.3 Morphology, purity and crystallography of ZnO NPs 13
3.2.4 Exposure metric measurement 13
3.3 Exposure Dose 14
3.4 Experimental design 14
3.5 Preparation of bronchoalveolar lavage fluid (BALF) 15
3.6 Determinations of total protein levels, LDH levels, IgE level and inflammatory cell profiles 16
3.7 Determination of pro-inflammatory mediators 17
3.8 Histological analysis 17
3.9 Animal weight change 17
3.10 Statistical analysis 18
3.11 Multi-path particle deposition (MPPD) model 18
Chapter 4. Result 19
4.1 Characteristics of ZnO NPs and chambers condition 19
4.2 Results of the AAI experiment 20
4.2.1 Total protein levels, LDH levels in BALF and IgE level in serum 20
4.2.2 Inflammatory cell profiles in BALF 21
4.2.3 Pro-inflammatory mediators in the BALF 22
4.2.4 Histological analysis 22
4.2.5 Animal weight changes 23
4.3 Result of the adjuvant experiment 24
4.3.1 Total protein levels, LDH levels in BALF and IgE level in serum 24
4.3.2 Inflammatory cell profiles in BALF 25
4.3.3 Pro-inflammatory mediators in the BALF 25
4.3.4 Histological analysis 26
4.3.5 Animal weight changes 26
Chapter 5. Discussion 27
5.1 Allergic airway inflammation caused by ZnO NPs 27
5.1.1 Time course 29
5.2 Allergic adjuvant effect of ZnO NPs 30
5.3 Weight changes 30
5.4 Estimation of actual exposure dose 31
5.5 Limitations of study 35
Chapter 6. Conclusion 37
Chapter 7. Recommendations 38
Chapter 8. Reference 39


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