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研究生:張淳昭
研究生(外文):Chuen-Chau Chang
論文名稱:空氣懸浮微粒在自發性高血壓大鼠上之心律調節效應研究
論文名稱(外文):CARDIOREGULATORY EFFECTS OF PARTICULATE MATTERS ON SPONTANEOUSLY HYPERTENSIVE RATS
指導教授:鄭尊仁鄭尊仁引用關係
指導教授(外文):Tsun-Jen Cheng
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:2006
畢業學年度:94
語文別:中文
論文頁數:156
中文關鍵詞:空氣污染空氣懸浮微粒心血管疾病心跳速率變異性分析生理訊號遙測術自發性高血壓大鼠
外文關鍵詞:Air pollutionParticulte matterCardiovascular diseaseHear rate vairabilityRadiotelemetrySpontaneously hypertensive rats
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許多流行病學研究指出,空氣中氣懸微粒的增加與心血管疾病死亡率增加有關,更進一步的流行病學觀察則注意到氣懸微粒的增加與心血管疾病相關的住院率、急診處到訪率、心律不整發生率、以及急性心肌梗塞的促發等有相當的相關性,然而確實致病機轉仍不清楚。近年來,越來越多研究試圖以毒理學的方式為氣懸微粒的心血管毒性提供合理的解釋,並且也為其間的機轉提供了一些說明。不過這些毒性與大氣微粒物理化學特性之相關還不是很清楚,特別是心血管毒性方面的資料更少。綜合流行病學的觀察,以及毒理學的動物實驗結論,美國心臟醫學會(American Heart Association)在2004年為氣懸微粒的心血管毒性勾勒出幾個可能的生物機轉,包括兩大方面:局部與全身性發炎反應及其所促發的血栓成形、加速動脈粥狀硬化、和動脈血管異常收縮;自主神經調節失常及其所導致的心律不整和心臟功能衰竭。
為了更進一步了解微粒性空氣污染引發心血管毒性的可能作用,從而提供公共衛生上疾病預防以及空氣污染控制的政策依據,我們實在有必要建立毒理學的證據及釐清其中可能的作用機轉。本研究的目的,主要是聚焦在氣懸微粒與自主神經調節失常的環節上,嘗試以毒理學的原理與研究架構,探討微粒性空氣污染在自發性高血壓大鼠所引發的心血管毒性。此外,我們也探討了某些微粒成分單獨暴露以及同時暴露時的效應差異,嘗試著由交互作用的觀點解釋微粒性空氣污染引發心血管毒性的可能作用。
我們首先利用鼻部暴露腔(Nose-only exposure chamber)重複呼吸暴露的方式,在位於桃園縣中壢市的環境保護署環境檢驗所,以植入生理遙測儀(Radiotelemeter)之自發性高血壓大鼠(Spontaneously hypertensive rats, or SH rats)檢測經過微粒濃縮器(Ultrafine particle concentrator, UFPC)濃縮之細粒徑空氣懸浮微粒(PM2.5)在心血管系統的毒性效應。經過Mixed effect models修正重複測量干擾以及調整相關變因後,發現濃縮的細粒徑微粒暴露期間會升高心跳﹝達51.6bpm (p<0.001)﹞、平均體循環血壓﹝8.7mmHg (p=0.002)﹞及心肌收縮力(Myocardial contractility)等循環系統相關參數,初步證實實驗模型的有效性,以及心肌收縮力在微粒心血管毒性研究中的可用性,並且為後續的自主神經功能研究指引一個方向。在更進一步的數據分析中,我們以時間義域(Time domain)的心跳速率變異性(Heart rate variability, HRV)來代表自主神經系統的調節功能,其結果顯示在濃縮的細粒徑微粒暴露開始時會有降低SDNN達15%的現象,隨著暴露時間的增加SDNN會有逐步降低的現象,並且在5小時暴露結束時降到最低值40%,此一過渡性效應在結束暴露後6到8小時內會恢復到暴露之前的水準。另外一方面,代表副交感神經活性的RMSSD也在暴露期間有較小幅度的降低現象。此一研究結果支持我們的假設,即微粒的暴露可能經由自主神經系統失衡的機轉,造成其心血管的毒性表現。
沙塵暴是強風捲起大量沙塵,使能見度惡化的沙塵天氣,基本上是乾旱與沙漠化氣候環境的產物。台灣地區位處大陸沙塵暴下游區域,大陸強沙塵發生時,在有利的大氣長程傳送條件下,台灣的空氣品質會受到影響,其現象主要是空氣中懸浮物質突然增加,在短時間內造成大規模空氣品質惡化。但是,沙塵暴是否會造成健康危害仍然是學界極感興趣的議題。為了印證這一套新開發方法學的可用性,同時為了了解亞洲沙塵暴的心血管效應,我們也應用這套系統探討了亞洲沙塵暴期間所收集到微粒的急性效應。其結果顯示,自發性高血壓大鼠在暴露於沙塵暴濃縮微粒的5小時期間,同樣會有心跳、平均血壓、以及心肌收縮力增加的現象。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心血管效應,對於學界關於沙塵暴健康效應的認識提供了進一步的論據。
另外一方面,在證實空氣污染懸浮微粒的暴露可能經由自主神經系統失衡,造成其心血管毒性的機轉之後,更令學界急切想釐清的是懸浮微粒內容成分與其毒性效應之間的關係。由流行病學的研究可以看出,懸浮微粒空氣污染所造成的心血管系統毒性並不盡相同。不同粒徑與不同內容成份的微粒暴露,其所造成的心血管效應,不論是總體死亡率、罹病率、住院率、以及急診室到訪率等,皆有不同的表現。即以人體的心跳速率變異性分析而言,在懸浮微粒空氣污染期間所測得的RMSSD竟然有升高與降低兩種截然不同的觀察結果。而在毒理學的研究裡,濃縮懸浮微粒所造成實驗動物的心跳速率改變和心律不整的發生並非很一致的發生。另外有些實驗動物的心跳速率變異性和實驗時的風向有很好的相關性。這些跡象在在顯示懸浮微粒之心血管毒性效應與其內容成分有很大的相關性。至於是何種成分扮演何種角色、各種成分之間是否有交互作用等等問題則屬有待回答的範疇。我們推測不同粒徑大小的碳核心(Carbonaceous Cores) 以及過渡金屬成分,特別是鐵(Fe)和鎳(Ni),可能是導致心血管毒性不同的原因之一。我們藉由在自發性高血壓大鼠身上進行氣管灌注(Intratracheal Instillation, IT)的方式,研究包括懸浮在0.25ml PBS中的14奈米碳黑(ultrafine carbon black 14 nm, ufCB; 1435μg/kg, n=4; and 2870μg/kg, n=4)、280奈米碳黑(fine carbon black 280 nm, fCB; 1435μg/kg, n=5; and 2870μg/kg, n=5)、鐵(105μg/0.25ml, n=5; and 210μg/0.25ml, n=3)和鎳(263μg/0.25ml, n=5; 526μg/0.25ml, n=3)等PM成分的心血管效應。另外,為了進一步了解成分間的交互作用,我們也探討了ufCB (2870μg/kg)合併暴露鐵(105μg/0.25ml, n=4)以及ufCB (2870μg/kg)合併暴露鎳(263μg/0.25ml, n=4)的心跳速率變異性分析。其結果顯示,氣管灌注高低兩個劑量的超細粒徑碳黑ufCB後18到30小時會有ANN降低而伴隨SDNN升高的現象,RMSSD的變化則較不顯著。而氣管灌注高低兩個劑量的細粒徑碳黑fCB後,在72小時的觀察期間ANN、SDNN、以及RMSSD等參數則無顯著變化。雖然低劑量的鎳在觀察的最後24小時會有增加ANN、以及RMSSD等兩個參數的趨勢,但其變化幅度相對較小;高劑量的鎳則可以在72小時的觀察期間,產生相當明顯先升後降的兩相性(Biphasic)變化。另外,低劑量的鐵可以在觀察的最後24小時升高ANN、SDNN、以及RMSSD等三個參數達到顯著水準,但其變化幅度相對較小;高劑量的鐵則可以在72小時的觀察期間,在ANN、以及RMSSD等兩個參數產生類似於高劑量鎳明顯先升後降的兩相性變化,而在SDNN的效應則是雙峰式的變化。另外一方面,高劑量的超細粒徑碳黑ufCB與低劑量鐵和鎳合併暴露的結果,則會在觀察期間的後半段產生超乎預期的效應,顯示交互作用明顯。此一研究結果顯示,PM的不同成分可以引發不同的心血管反應;而即使是單一成份的暴露,也可能在不同的階段表現出不同的心血管反應;另外,兩種成分合併暴露時會有明顯的交互作用發生。
這項研究結果將可增進我們對空氣污染懸浮微粒心血管毒性機轉的瞭解,對於預防微粒相關疾病及法規制訂將有所助益。
Air pollution has been associated with cardiovascular diseases in epidemiology, but the underlying mechanisms remained to be explored. We applied heart rate variability (HRV) on spontaneously hypertensive rats (SHR) receiving particulate matters (PM) or their major components to demonstrate the biological plausibility.

In the first part of the thesis, concentrated ambient particles (CAPs) were inhaled by radiotelemtered SHR via nose only exposure system. Statistical analysis revealed increased heart rate, mean blood pressure, and myocardial contractility during the exposure hours. Concurrent decreases in the 5-minute standard deviation of the normal-to-normal intervals (SDNN) and the 5-minute root mean square of successive differences of adjacent normal-to-normal intervals (RMSSD) were also demonstrated. These findings were also observed in exposures to CAPs collected during an episode of Asian dust storm.

In the latter part of the thesis, ultrafine carbon black (ufCB, 14 nm), fine carbon black (fCB, 280 nm), Fe2(SO4)3 and NiSO4 were all exposed to SHR via intratractheal instillation at two doses. The results showed little changes of heart rate and HRV indices during fCB exposures. Dynamic changes were observed in exposures to ufCB, Fe and Ni. Obvious interactions were also demonstrated during combined exposures to ufCB and Fe or Ni.

We conclude that CAPs inhalation may increase heart rate, blood pressure, and myocardial contractility in spontaneously hypertensive rats. The study also shows that QAI, which reflexes the myocardial contractility, may be a sensitive and useful indicator in the study of PM-related cardiovascular toxicity. This set of outcome measurements is capable of demonstrating the cardiovascular toxicities of CAPs collected during an episode of Asian dust storm.
Aside from the alterations in heart rate, blood pressure, and myocardial contractility, CAPs inhalation may also alter cardiac autonomic function, resulting in changes in heart rate variability (HRV) parameters including SDNN and RMSSD. HRV measurements, on the other hand, are sensitive enough to demonstrate the phasic changes and the interactions of toxic responses induced by ufCB and transition metals instillation. Conversely, interactions among multiple copollutants might be important in the synthesis of air pollution health effects, and that mathematical summation of componential toxic responses might not be enough in the estimation of real life exposure.
ABSTRACT 4
1. INTRODUCTION 8
1.1 SPECIFIC AIMS 8
1.2 BACKGROUNDS AND SIGNIFICANCES 9
1.2.1 Epidemiology of Particulate Matter Health effects 9
1.2.2 Epidemiologic Evidences of Particle-Induced Cardiovascular Toxicity 10
1.2.3 Toxicological Evidences of Particle-Induced Cardiovascular Toxicity 15
1.2.4 Componential Effects of Particulate Matter 19
1.2.5 Diseased Animal Models in Particulate Toxicology 20
1.3 OVERALL EXPERIMENTAL APPROACHES 21
1.3.1 Animal Subjects 21
1.3.2 Radiotelemeter and Data Acquisition 22
1.3.3 Particles and Exposure Routs 23
1.3.4 Outcome Measurements 24
1.3.5 Experimental Designs and Statistics 27
2. CARDIOVASCULAR EFFECTS OF CONCENTRATED AMBIENT PARTICULATE MATTERS 31
2.1 CONCENTRATED AMBIENT PARTICLES ON HEMODYNAMICS 31
2.1.1 Abstract 31
2.1.2 Introduction 32
2.1.3 Materials and Methods 33
2.1.4 Results 37
2.1.5 Discussion 39
2.1.6 Tables and Figures 44
2.2 CONCENTRATED AMBIENT PARTICLES ON CARDIOREGULATORY FUNCTION 47
2.2.1 Abstract 47
2.2.2 Introduction 48
2.2.3 Materials and Methods 49
2.2.4 Results 53
2.2.5 Discussion 55
2.2.6 Tables and Figures 59
2.3 HEMODYNAMIC EFFECTS OF DUSTORM PARTICLES 63
2.3.1 Abstract 63
2.3.2 Introduction 63
2.3.3 Materials and Methods 64
2.3.4 Results 67
2.3.5 Discussion 69
3. CARDIOVASCULAR EFFECTS OF COMPONENTS IN AMBIENT PARTICLES 75
3.1 CARDIOREGULATORY EFFECTS OF MAJOR AMBIENT PARTICLE COMPONENTS 75
3.1.1 Abstract 75
3.1.2 Introduction 78
3.1.3 Materials and Methods 88
3.1.4 Results 92
3.1.5 Discussion 93
3.1.6 Tables and Figures 101
4. DISCUSSIONS AND CONCLUSION 123
4.1 Overall research findings 123
4.2 Biologic plausibility of PM associated cardiovascular effects 124
4.3 Limitations 127
4.3.1 Telemetry associated 127
4.3.2 Experimental facility associated 127
4.3.3 Experimental designs 128
4.3.4 Exposure particles and routes 128
4.3.5 Animal models 129
4.3.6 Outcome measurements 130
4.4 Conclusion 131
5. REFERENCES 133
6. APPENDICES 156
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