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研究生:雷侑蓁
研究生(外文):Yu-Chen Lei
論文名稱:空氣懸浮微粒心肺毒性研究
論文名稱(外文):CARDIOPULMONARY TOXICITY STUDY OF AMBIENT PARTICULATE MATTERS
指導教授:鄭尊仁鄭尊仁引用關係
學位類別:博士
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:2005
畢業學年度:93
語文別:英文
論文頁數:185
中文關鍵詞:空氣懸浮微粒心肺毒性
外文關鍵詞:cardiopulmonary toxicityambient particulate matters
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流行病學研究顯示,微粒空氣污染對心肺疾病的毒性效應是公共衛生上相當重要的議題,然而生物學上的可能性仍不清楚。近年來越來越多探討微粒空氣污染的毒理研究嘗試回答這個問題。研究顯示,微粒空氣污染中的特定成分,如酸鹽、金屬、內毒素,或是微粒本身的特性,如粒徑、表面積、表面活性等都可能與健康效應有關。最近的研究進一步指出,個體本身的易感受性也可能與微粒空氣污染造成的健康效應有關,流病研究發現,老人、小孩及本身患有呼吸道或心血管疾病的人對微粒空氣污染的影響較為敏感,最近的研究更顯示,糖尿病患可能是另一個與微粒空氣污染引發的心血管疾病有關的易感族群,然而詳細的生物機轉仍須進一步驗證。
為了釐清微粒空氣污染造成心肺毒性的生物可能性,提供公共衛生上疾病預防及污染控制的政策依據,我們必須建立毒理學證據及釐清可能的機轉。本研究的目的,嘗試以呼吸毒理學的架構及原理,探討微粒空氣污染的呼吸道與心血管毒性,分別以肺部疾病及心血管疾病動物模式,釐清微粒空氣污染的健康效應。此外,我們亦探討了微粒的粒徑所可能扮演的角色,包括細粒徑微粒(PM2.5)及奈米粒徑微粒(<100nm)。
首先,我們建立微粒空氣濃縮器及動物暴露系統進行呼吸暴露,以Monocrotaline(MCT)-肺高血壓大鼠為肺部疾病動物模式,探討暴露位於交通繁忙台北都會區的環保署超級測站附近濃縮細粒徑微粒(PM2.5)的急性肺部效應,同時應用此套系統,探討暴露於沙塵暴其間濃縮微粒的急性效應。研究結果顯示,肺高血壓大鼠在急性暴露台北都會區濃縮微粒後,會引發顯著的肺部傷害與發炎,發炎前趨細胞激素亦增加。而肺高血壓大鼠在暴露於沙塵暴濃縮微粒6小時,即會產生顯著的肺部發炎,同時周邊血液白血球亦有增加的趨勢,這些急性毒性效應與沙塵暴的濃度呈現劑量反應關係。本研究發現,台北都會區與沙塵暴其間微粒成分並不完全相同,台北都會區有較高比例的酸鹽,而沙塵暴其間微粒則有較高比例的矽及鋁等元素,特定成分與健康效應的關係需要進一步的研究。本研究首次發現,沙塵暴微粒可能在敏感的疾病動物上造成急性的肺部效應,可能與黏附於沙塵暴微粒上的污染物、內毒素,或是沙塵暴微粒中小粒徑微粒數目濃度較高有關。使用微粒濃縮器可以真實反應大氣微粒的組成,但無法釐清微粒粒徑的影響,最近研究指出,大氣微粒中奈米粒徑的微粒可能與健康效應有關,因此我們以人造的聚苯乙烯微粒,粒徑包括64、202及535 nm,探討微粒粒徑對於肺部毒性的角色。我們發現,在氣管灌注同一質量濃度24小時後,64 nm微粒造成的肺部發炎與傷害、細胞激素的增加都較205及535nm的微粒顯著,奈米微粒也會造成較明顯的氧化壓力,包括肺部glutathione (GSH)的下降及血漿中8-OHdG的增加。進一步分析顯示,這些急性效應與所灌注的微粒總表面積有相關。我們認為微粒引發的肺部效應中,除了粒徑效應之外,總表面積亦可能扮演重要角色。
除了肺部毒性之外,微粒有關的心血管毒性也成為重要的議題。然而過去應用於微粒毒性研究的心血管疾病動物模式都存在其限制性。我們發現,糖尿病的部分病理生理變化可能與微粒引發的心血管效應有共同的作用途徑,包括氧化壓力的增加、系統性的發炎反應及血管內皮功能的改變,因此我們首度嘗試以strepotozotocin誘發之糖尿病大鼠作為微粒毒性研究的心血管疾病動物模式,探討微粒暴露的影響,並評估此模式應用於微粒心血管毒性研究的可行性。考量應用微粒濃縮器及鼻部暴露腔的侷限空間,可能對心血管參數造成影響,因此我們以氣管灌注的方式,探討於台北都會區超級測站收集的細粒徑微粒(PM2.5)的心血管效應。結果顯示,PM2.5的暴露造成健康及糖尿病大鼠的肺部發炎反應,然而此肺部相關效應並不會因為糖尿病的有無而有所不同。有趣的是,我們發現暴露於PM2.5的糖尿病大鼠血中氧化壓力標記8-OHdG增加了15.6%,而健康大鼠只增加4.0%;更值得注意的是,糖尿病大鼠在暴露後PM2.5,血中內皮素(ET-1)增加了40.3%,而健康大鼠僅增加了2.6%。經進一步統計分析,我們發現微粒暴露與糖尿病對於8-OHdG (p<0.01)及ET-1(p=0.08)的增加有交互作用。進一步探討奈米粒徑的暴露對糖尿病大鼠的心血管效應,發現暴露於奈米碳黑(14nm)導致顯著的肺部發炎及傷害反應,奈米碳黑在糖尿病大鼠造成顯著的周邊發炎反應增加,血管內皮素升高及血液一氧化氮降低,奈米微粒暴露可能在糖尿病的病理生理作用途徑造成心血管疾病風險的增加。
本研究結果,證實了微粒空氣污染中的細粒徑微粒(PM2.5)在疾病動物模式可造成心肺毒性效應,同時我們發現奈米微粒在微粒引發的呼吸及心血管毒性可能扮演重要的角色。本研究提供過去流行病學觀察的支持,並認為可進一步應用糖尿病大鼠於微粒相關心血管疾病的研究,對於生物機制可提供有用的資訊,並提供未來研究的新方向。

An increasing amount of epidemiological evidences suggest that the effect of particulate air pollution on the cardiopulmonary system is a significant public health concern. However, the biological plausibility remains unclear. Recently, the cardiopulmonary toxicities of particulate matter (PM) are under active investigation. Studies suggest that specific components of PM are responsible for the related toxicity, such as acidity salts, metals and endotoxin. The characteristics of PM may also be associated with adverse effects, such as particle size, surface area and the surface activity. Recent studies further indicate that the susceptibility of subjects exposed to PM is associated with PM-induced health effects. Epidemiologic studies report that the elderly, children and subjects with pre-existing respiratory and cardiovascular disease are more susceptible to PM. Recent investigations further indicate that diabetics may be another susceptible population in PM-related cardiovascular events. However, the exact biological mechanisms still need to be clarified.
In order to investigate the biological plausibility of PM-induced toxicity, and to provide evidence in public health and pollution control, it is necessary to establish the link between PM exposure and toxicological evidence. The aim of this study is to apply the principles of inhalation toxicology in investigating PM-induced pulmonary and cardiovascular toxicity. We used pulmonary and cardiovascular diseased animal models to examine the acute effects after exposed to fine particles (PM2.5) and ultrafine particles (<100nm).
At fist, we set up ambient particle concentrator and animal inhalation exposure system. Using monocrotaline (MCT)-induced pulmonary hypertensive rats as pulmonary diseased animals, we investigated the acute effects after exposed to PM in a traffic busy area near EPA supersite in Taipei city and to PM during Asian dust events. Our results revealed, significant pulmonary inflammation and injury, and increase in proinflammatory cytokine were observed in MCT-pulmonary hypertensive rats exposed to PM in traffic busy area. We also found a significantly increased pulmonary inflammation and WBC in peripheral blood in MCT-pulmonary hypertensive rats exposed to PM during Asian dust events for only 6 hours. There was a dose-response relationship between this observation and the concentration of Asian dust events. We found the components of PM in traffic busy area and PM during dust storm were not identical. PM in traffic busy area contained higher proportion of sulfate, however, PM during dust storm consisted largely of silica and aluminum. It is not clear whether these different components were responsible for the pulmonary toxicity. This was the first report that PM during dust storm caused pulmonary toxicity on diseased animals. We suggested these effects might be associated with the absorbed pollutants and endotoxin on PM, or be associated with the higher number concentration of smaller particles. Using state of art ambient particle concentrator can reflex the nature of ambient particles, however it has the limitation in differentiating specific particle size. Recent studies indicate that ultrafine fraction of ambient PM may be responsible for the adverse health effects. We used artificial polystyrene particles, including 64, 202 and 535nm, to examine the effect of particle size on pulmonary toxicity. We found after intratracheally instilled with same mass concentration, ultrafine particle (64nm) resulted more significant pulmonary inflammation and injury as compared to larger particles (202 and 535nm) in MCT-pulmonary hypertensive rats. Moreover, exposed to ultrafine particles caused significant oxidative stress, including depletion of glutathione (GSH) in lung tissue, and increase in plasma 8-OHdG. Further analysis revealed that these effects were associated with instilled total particle surface area. We suggested that not only particle size, but the surface area of PM might play important role on PM-induced pulmonary toxicity.
In addition to pulmonary toxicity, PM-induced cardiovascular toxicity becomes concerning issue. However, cardiovascular diseased animals in previous studies have some limitation. We found pathophysiology of diabetes might share the common pathway with PM-induced cardiovascular events, including excess generation of oxidative stress, systemic inflammation and vascular endothelial dysfunction. Therefore, we firstly used strepotozotocin (STZ)-diabetic rat as cardiovascular diseased animal model in PM-related study. To avoid possible confounding factors in the confined space of nose-only exposure chamber, we used the method of intratracheal instillation to investigate the cardiovascular toxicity after treatment with PM2.5 collected in a traffic busy area near Taipei EPA supersite. The results revealed that exposure to caused pulmonary toxicity in both diabetic and healthy rats, and the extent of these effects didn’t be modified by the status of diabetes. Interestingly, we found that increases of 8-OHdG and ET-1 were more prominent in diabetic rats. For 8-OHdG generation, diabetic rats exposed to PM demonstrated a 15.6 % increase; however, non-diabetic rats exposed to PM showed only 4.0 % increase. A 40.3 % increase in plasma ET-1 after PM exposure was observed in diabetic rats, while there was only a 2.6 % increase in plasma ET-1 after PM exposure in non-diabetic rats. General linear model was further used to test the interaction between diabetes and PM. We found there were interactions on 8-OHdG (Table 3.1.4, p<0.01) and ET-1 (p=0.08). We further investigated the effects of ultrafine PM on diabetic rats. We found ultrafine carbon black (14nm) caused significant pulmonary inflammation. Exposed to ultrafine carbon black further resulted in significant increase of systemic inflammation, increase of ET-1 and decrease of NO in diabetic rats.
Our results demonstrated that biological plausibility that fine particles (PM2.5) would cause cardiopulmonary toxicity in compromised diseased animals. We also found ultrafine particles might play important role on PM-induced cardiopulmonary effects. This study provided toxicological supports for previous epidemiologic observations. We further believed that STZ-diabetic rat could be further applied in the mechanistic studies of PM-induced cardiovascular events.


TABLE OF CONTENTS i
ACKNOWLEDGEMENT iii
CHINESE ABSTRACT iv
ABSTRACT vii
1. INTRODUCTION 1
1.1 Overall research objectives 1
1.2 Backgrounds 4
1.2.1 Epidemiology of Particulate Matter Health Effects 4
1.2.2 Pulmonary toxicity of particulate matter 5
1.2.3 Cardiovascular effects of particulate matter 9
1.2.4 Potential role of specific components of particulate matter 11
1.2.5 Diseased animals in particulate matter toxicity studies 13
1.3 Overall experimental approaches 20
2. PULMONARY TOXICITY OF AMBIENT PARTICULATE MATTERS 22
2.1 Pulmonary effects of fine particles in MCT-pulmonary hypertensive rats 22
2.1.1 Abstract 22
2.1.2 Introduction 23
2.1.3 Materials and methods 26
2.1.4 Results 29
2.1.5 Discussion 31
2.1.6 Tables and figures 34
2.2 Pulmonary effects of ultrafine particles in MCT-pulmoanry hypertensive rats 40
2.2.1 Abstract 40
2.2.2 Introduction 41
2.2.3 Materials and methods 43
2.2.4 Results 45
2.2.5 Discussion 47
2.2.6 Tables and figures 49
3. CARDIOVASCULAR TOXICITY OF AMBIENT PARTICULATE MATTERS 54
3.1 Cardiovascular effect of fine particles in STZ-diabetic rats 54
3.1.1 Abstract 54
3.1.2 Introduction 55
3.1.3 Material and methods 56
3.1.4 Results 61
3.1.5 Discussion 62
3.1.6 Tables and figures 68
3.2 Cardiovascular effect of ultrafine particles in STZ-diabetic rats 70
3.2.1 Abstract 70
3.2.2 Introduction 70
3.2.3 Materials and methods 73
3.2.4 Results 76
3.2.6 Tables and figures 79
4. DISCUSSION AND CONCLUSION 83
5. REFERENCES 89


Appendix 1 Effects of dust storm particles on inflammation markets in pulmonary hypertensive rats. Environ Res. 2004; 95: 71-76
Appendix 2 Effects of concentrated ambient particles on airway responsiveness and pulmonary inflammation in pulmonary hypertensive rats. Inhal Toxicol. 2004; 16: 785-792
Appendix 3 Enhanced oxidative stress and endothelial dysfunction in streptozotocin-diabetic rats exposed to fine particles. Environ Res (in revision)
Appendix 4 Association of particle surface area with oxidative stress, lung inflammation and oxidative DNA damage in pulmonary hypertensive rats. Toxicology Letters (submitted)
Appendix 5 DNA single strand breaks in peripheral lymphocytes associated with urinary thiodiglycolic acid levels in polyvinyl chloride workers. Mutat Res. 2004; 561: 119-126.
Appendix 6 Effects on sister chromatid exchange frequency of polymorphisms in DNA repair gene XRCC1 in smokers. Mutat Res. 2002; 519: 93-101


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洪春量,以微粒濃縮器探討懸浮微粒對天竺鼠肺部健康之影響,國立陽明大學/環境衛生研究所,2003
鄭伊玲,肺部上皮內襯液體對於微粒引起氧化傷害之影響,國立台灣大學/職業醫學與工業衛生研究所,2004

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