博碩士論文 104326003 詳細資訊



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姓名 陳盈均(Ying-Jyun Chen)  查詢紙本館藏   畢業系所 環境工程研究所
論文名稱 香菸煙霧微粒的物理特性對肺部沉積模式之影響並應用於慢性阻塞性肺病小鼠模型
(Effects of Cigarette Smoke Particles Properties on Lung Deposition Models and Application in Mice COPD Model)
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摘要(中) 菸煙霧一般可分為煙霧由濾嘴端吸入到人體肺部之主流煙（Mainstream Smoke，簡稱MS），而從燃燒端直接釋放至環境和透過吸菸者呼出的煙氣則稱為側流煙（Sidestream Smoke，簡稱SS）。香菸煙霧是公認具有危害健康風險，組成相當複雜，迄今為止已有7000多種的化合物被鑑定出來。除化學成分外，微粒的尺寸、數目濃度、表面積、形狀和電性都可能影響呼吸暴露微粒的健康效應。為評估香菸煙霧微粒於肺部區域暴露劑量，常利用兩個肺部沉積數學模式（ICRP和MPPD）進行估算，模式中考慮呼吸參數、微粒特徵和肺部形態。至今已有許多研究探討香菸煙霧微粒各別的物化特性及肺部沉積積率，然而仍缺乏整合性的實驗數據。本研究將綜合量測香菸煙霧微粒的各項氣膠物化特性（包含微粒粒徑分佈、質量濃度、黑碳濃度、微粒沉積於肺泡區之微粒表面積濃度及微粒有效密度等），並進行特徵分析。探討主流菸及側流菸於肺部不同沉積位置之沉積積率，並應用於小鼠暴露模型。另外，香菸煙霧是造成慢性阻塞性肺病的重要危險因子。許多研究已指出暴露於香菸微粒下，自噬作用會加重肺部上皮細胞的老化、死亡、纖毛功能不良並導致肺氣腫的形成。醣皮質固醇為治療COPD重症患者常使用的抗發炎藥物，其中醣皮質固醇藥物與自噬作用之調控有關，但是目前COPD患者使用醣皮質固醇藥物與自噬作用之間的關聯性並不清楚。因此本研究嘗試建立COPD動物模式，並模擬使用醣皮質固醇藥物進行治療，其後研究肺部上表皮細胞自噬作用的表現與其調控機轉，所得資訊可供未來COPD患者藥物使用的參考。
經比較肺部沉積模式所估計及AeroTrak儀器實驗所測得的沉積肺泡區之微粒表面積濃度，可計算一微粒形狀因子（Ks），其結果指出SS香菸煙霧微粒之形貌近似於球形。此外，為避免香菸微粒聚集或老化影響，本研究除以傳統DMA-APM系統進行量測外，另建置APM-SMPS實驗方法提高量測之時間解析度。實驗結果發現側流煙及主流煙香菸煙霧微粒有效密度皆不受粒徑影響，此顯示主流煙亦為球形微粒。本研究亦改良Ning等人之方法，即時量測各不同粒徑下的BC、UVPM濃度，解析不同燃燒機制所致之側流煙及主流煙香菸煙霧微粒。以實驗所得之測值，並利用MPPD模式評估小鼠吸入主流煙及側流煙霧微粒各區域之沉積積率: 頭部沉積機率為0.52、0.47；支氣管各別為0.02、0.03；肺泡各別為0.01、0.04；肺部總合各別為0.55、0.54。當沉積劑量公式分別計算以吸入微粒數及表面積沉積量表示時，可發現以微粒沉積量較高者為吸入側流煙微粒，而表面積則以主流煙微粒較高。兩者之沉積積率整體差異不大，但吸入主流煙微粒表面積沉積量卻比側流煙高出5倍，此緣於側流煙及主流煙的微粒粒徑分佈差異。因此表示單看DF並不能代表吸入微粒沉積之情形，需考量其他因素。
小鼠暴露香菸煙霧微粒後犧牲並收集肺部組織，經由毒理分析（Total Protein、LDH、8-Isoprostane、IL-8、Western Blot）評估肺部組織的發炎反應及COPD小鼠自噬作用的表現是否與醣皮質固醇有關。本研究發現使用醣皮質固醇之COPD小鼠LC3BⅡ/Ⅰ之比值較無使用低，顯示出COPD小鼠的自噬作用功能異常。當自噬作用被抑制時，使用醣皮質固醇會增加LDH、8-isoprostane及IL-8的表現，雖然在統計上無顯著之差異。但是由先前的研究得知自噬作用與IL-8濃度相關，並且抑制自噬作用後，會使IL-8濃度下降。其本研究IL-8及LC3BⅡ/Ⅰ的比值卻是增加的，顯示醣皮質固醇活化自噬作用的能力；當自噬作用被活化時，使用醣皮質固醇刺激會發現LC3BⅡ/Ⅰ之比值增加，顯示Autophagy應移除累積的有害物質，降低ROS的產生及抑制發炎反應，但是8-isoprostane及IL-8濃度並無下降，表示產生過多或功能不良的Autophagy，反而無法使自噬作用產生保護機制。醣皮質固醇抑制發炎反應的能力下降並且增加肺部之氧化壓力，都顯示出COPD小鼠的自噬作用功能異常，導致COPD小鼠對醣皮質固醇的易感受性下降。
摘要(英) Tobacco smoking is a recognized risk to human health, and more than 7000 chemical compounds have been identified. Moreover, cigarette smoking has been considered to be a risk factor for developing chronic obstructive pulmonary disease (COPD), which is an important health problem in the world. Mainstream cigarette smoke (MS) is a major concern for smokers, and the sidestream cigarette smoke (SS) could influence the neighboring people through passive smoking. In addition to the chemical composition, particle size, number concentration, surface area, morphology and charging status might also be important parameters affecting the health effects and the deposition fraction in the respiratory system. To estimate the inhalation dose of cigarette smoke particles in different regions of the lung, international commission on radiological protection model (ICRP) and multiple path particle dosimetry model (MPPD) are generally used and the aerosol physical properties were required as input parameters, which, however, were not comprehensively investigated in the past. In this study, the aerosol physical properties of cigarette smoke particles (including particle size distribution, mass concentration, concentration of black carbon, particle surface area concentration deposited in the alveolar region and effective particle density) are thoroughly characterized and studied for the dose of respiratory deposition, and applied to mice exposure model. To avoid the effects of cigarette smoke particles coagulation or aging, the measurements were mostly performed in situ and reported in real-time. The effective density of MS and SS cigarette particles was measured by both traditional DMA-APM system and APM-SMPS system (with improved temporal resolution). The effective particle density was found to be independent of particle mobility size, which suggested that the particles could be spherical. The novel tandem DMA-AE33 system was established to provide the size-selective BC and UVPM mass concentrations of cigarette smoke. These parameters were used for calculating the deposition fraction of cigarette smoke in MPPD. The results show the deposition fraction of mice for MS particles were 0.52, 0.02, 0.01 and 0.55 for head, trachea and bronchi (TB), alveoli and total region, and those for SS particles were 0.47, 0.03, 0.04 and 0.54. Some of these aerosol characteristics of cigarette smoke particles are first time being revealed and valuable for lung deposition and inhalation toxicity studies.
The smoker’s inflammatory cells would increase lung epithelial cells’ ageing, death, poor cilia function and the formation of emphysema, and regulation of autophagy is associated with them. Clinically, glucocorticoid is commonly used for severe COPD with acute exacerbation; however, glucocorticosteroids insensitivity is often occurred in severe COPD. Our study to investigate the association between used corticosteroids treatment and lung inflammation in mice. After exposure, we collected lung tissue of mice to study the biological responses (Total Protein、LDH、8-Isoprostane、IL-8、Western Blot). LC3BⅡ/Ⅰ ratio was significantly reduced by use of glucocorticoid in COPD mice. The results suggest that COPD mice were insensitive to glucocorticosteroid. When autophagy was inhibited by 3-Methyladenine (3MA), there were no significant increased in LDH, 8-isoprostane and IL-8 by glucocorticosteroid. Previous researches indicated that when autophagy was inhibited by 3-MA, there was reduced in IL-8. Therefore, our study levels of IL-8 and LC3BⅡ/Ⅰ ratio were significantly increased by glucocorticosteroid at COPD mice. When autophagy was activated by Torin 1, there was increased in LC3BⅡ/Ⅰ ratio by glucocorticosteroid, To indicate the Autophagy helped to remove accumulated harmful substances, reduce the production of ROS and inhibit inflammation, but there were no reduced in 8-isoprostane and IL-8.The results show an association between autophagy and glucocorticosteroid in inflammation, which could be applied to glucocorticosteroid insensitivity in COPD mice. In conclusion, autophagy may regulate glucocorticoid sensitivity in COPD.
關鍵字(中) ★ 香菸煙霧微粒
★ 物理特性
★ 肺部沉積模式
★ 慢性阻塞性肺病動物模型
★ 自噬作用
★ 醣皮質固醇		 關鍵字(英)
論文目次 摘要 I
ABSTRACT III
誌謝 V
目錄 VI
圖目錄 VIII
表目錄 X
第一章 前 言 1
1.1 研究動機 1
1.2 研究目的 2
第二章 文 獻 回 顧 4
2.1 香菸煙霧的特性 4
2.1.1 微粒化學成分 4
2.1.2 微粒粒徑分佈 14
2.1.3 微粒有效密度 21
2.1.4 微粒表面積 22
2.1.5 微粒帶電性 23
2.2 肺部沉積模式 25
2.3 慢性阻塞性肺病中自噬作用與類固醇藥物 27
2.3.1 類固醇藥物在慢性阻塞性肺病之發炎反應中扮演的角色 27
2.3.2 自噬作用 28
2.3.3 類固醇藥物對自噬作用可能的調控機轉 30
第三章 研 究 方 法 33
3.1 研究架構 33
3.2 量測實驗 34
3.2.1 系統設置 34
3.2.2 量測儀器原理與數據校正 35
3.3 暴露實驗 42
3.3.1 實驗系統 42
3.3.2 實驗流程 44
3.3.3 毒理分析 45
第四章 結 果 與 討 論 52
4.1 量測結果 52
4.1.1 香菸煙霧微粒分佈 52
4.1.2 香菸煙霧微粒質量與成分 56
4.1.3 香菸煙霧微粒肺部沉積表面積濃度 61
4.1.4 香菸煙霧微粒構形 63
4.1.5 香菸煙霧微粒電性 69
4.2 應用肺部沉積模式 70
4.2.1 多途徑微粒沉積（Multiple-Path Particle Deposition, MPPD）模式 70
4.2.2 評估沉積劑量 75
4.3 動物暴露實驗分析 80
4.3.1 曝露實驗量測結果 80
4.3.2 肺部組織毒理分析 81
4.3.3 小鼠病理切片分析 86
第五章 結 論 88
参考文獻(REFERENCE) 91
附件 108
口試委員意見回覆 109

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指導教授 蕭大智(Ta-Chih Hsiao) 審核日期 2018-3-23
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