臺灣博碩士論文加值系統

研究背景
吸菸為造成慢性肺阻塞病(chronic obstructive pulmonary disease, COPD)的重要因素之一。高遷移率族蛋白1 (high-mobility group box 1, HMGB1)為存在於大部分細胞中的DNA結合蛋白，被認為可以透過釋放到細胞外作為損傷相關分子模式(damage-associated molecular pattern molecules, DAMPs)誘導發炎相關反應，參與香菸誘導的肺損傷。電子煙做為香菸替代品，然而使用者接觸的有毒化物學物質可能與香菸煙霧中的有毒物質類似，更可能存在未知且有害的物質，而現今研究尚未了解電子煙霧對細胞毒性和發炎相關的機制。
研究目的
本研究探討電子煙霧對肺上皮細胞和肺巨噬細胞的細胞毒性，以及是否能影響細胞HMGB1的表現，並活化巨噬細胞的自噬作用。此外針對兩種煙產品含有的共同成分尼古丁，了解尼古丁是否能改變HMGB1表現和自噬作用的活化。最後探討電子煙液中的主要溶劑、電子煙裝置和煙液中的調味劑對細胞毒性的影響。
研究方法
本研究利用MTT assay分別檢測電子煙蒸氣提取物(e-cigarette vapor extract, EVE)、香菸煙霧提取物(cigarette smoke extract, CSE)和尼古丁對於肺上皮細胞和巨噬細胞的細胞毒性，再利用西方墨點法偵測HMGB1表現和巨噬細胞中自噬作用標記蛋白的表現。
研究結果
研究結果顯示EVE和CSE對A549上皮細胞和THP-1巨噬細胞都具有細胞毒性，而EVE在較低濃度便能引起細胞毒性。隨著給予EVE和CSE的濃度及給予的時間的上升，能使A549肺上皮細胞釋放出的HMGB1蛋白量增加；在THP-1巨噬細胞，HMGB1蛋白釋出和細胞內HMGB1蛋白表現量也隨給予的EVE和CSE濃度及給予的時間的上升而顯著增加，且自噬作用標記蛋白LC3B-II也顯著增加，而EVE在較低濃度就能引起以上的變化。以香菸和電子煙含有的共同成分尼古丁，直接給予THP-1細胞，結果發現尼古丁能促使THP-1巨噬細胞釋放出HMGB1蛋白增加、細胞內HMGB1和LC3B-II表現都顯著增加，但經換算，引發這些表現所需的尼古丁濃度遠大於EVE或CSE所含的尼古丁濃度。此外Propylene glycol (PG)和Vegetable glycerin (VG)之汽化煙霧對細胞毒性較小，且不同的電子煙裝置和含有不同調味劑的煙液所產生的煙霧，對細胞造成的毒性大小也不同。
結論
本研究發現EVE也會對細胞造成毒性，且比CSE造成的細胞毒性更高，也會促使巨噬細胞內HMGB1表現上升和大量釋出，並活化自噬作用，且效果也比CSE明顯。尼古丁也會促使以上現象的發生，但對照EVE或CSE所含之尼古丁尚未達到可引起反應之濃度，暗示EVE或CSE中可能有其他更容易促成巨噬細胞HMGB1蛋白表現上升和自噬作用活化的物質；若在收集更大量的煙霧或長期暴露於煙霧下，尼古丁仍可能參與引發細胞的發炎反應與自噬作用。另外，電子煙裝置或煙液調味劑也可能是影響電子煙霧引起細胞毒性的因素，未來需要更深入研究電子煙的其他成分或汽化後所產生的有毒物質造成的潛在危險。

Background
Smoking is one of the primary factors of chronic obstructive pulmonary disease (COPD). High-mobility group box 1 (HMGB1), a DNA-binding protein expressed in many cells, can serve as a regulator of autophagy and translocate outside the cell acting as a damage-associated molecular pattern molecule (DAMPs) to induce inflammatory responses. HMGB1 participates in cigarettes-smoke (CS) induced lung injury and may mediate the pathogenesis of COPD. E-cigarettes provide nicotine to addicts as alternatives for conventional cigarettes. Nevertheless, e-cigarettes still can be harmful and emit numerous toxicants. The mechanisms of cytotoxicity and inflammation induced by e-cigarettes have not been fully elucidated.
Objective
This study aims to investigate the cytotoxicity and inflammatory response of e-cigarettes vapor on lung epithelial cells and lung macrophages. We examine the expression of inflammation marker HMGB1 and its potential to activate the autophagy in macrophages. Furthermore, we assess the impact of nicotine, a common component in cigarettes and e-cigarettes, on the expression of HMGB1 and the activation of autophagy. Lastly, we evaluate the effects of main solvents in e-liquids, e-cigarette devices and flavorings in e-liquids on cytotoxicity.
Methods
EVE and CSE were exposed to A549 lung epithelial cells and THP-1 macrophages. Cytotoxicity in response to EVE, CSE and nicotine was measured by MTT assay in A549 cells and THP-1 cells, respectively. Inflammatory responses were measured by the levels of released and intracellular HMGB1 using Western blot. In addition, the autophagy marker, LC3B-II, was assessed following THP-1 cells exposed to CSE, EVE or nicotine.
Results
Although EVE and CSE induced cellular toxicity in both A549 cells and THP-1 cells, EVE can induce cytotoxicity in lower concentration than CSE. EVE increased either intracellular or released HMGB1 protein levels in THP-1 cells. Similar effects were observed with CSE. LC3B-II protein levels were also significantly elevated after EVE or CSE exposure. Additionally, EVE can cause inflammatory responses at lower concentrations compared to CSE. While the protein levels of HMBG1 and LC3B-II in THP-1 cells were influenced by direct treatment of nicotine, the required nicotine concentration is much higher than that contained in EVE or CSE, indicating that the extracts may contain other toxicants which are more likely to induce cellular responses than nicotine. The aerosolized propylene glycol and vegetable glycerin showed lower toxicity to THP-1 cells than EVE or CSE. In addition, different e-cigarette devices and e-liquid with different flavorings affect the e-cigarette induced cytotoxicity.
Conclusion
E-cigarettes vapor can induce cytotoxicity and HMGB1 release in both A549 cell and THP-1 cells, as well as the elevation of intracellular of HMGB1 and autophagy activation in THP-1 macrophages. It implies the harmful effect of e-cigarettes on lung injury. Although there might be other potent factors in EVE or CSE, nicotine may still be involved in triggering inflammatory responses and autophagy by treated with a larger amount of smoke or vapor collected samples or treated in longer exposure time. The choice of e-cigarette devices and various flavorings may impact the cytotoxicity of e-cigarettes. Other toxic substances generated by vaporization of e-cigarettes should be further studied in the future.

中文摘要 I
英文摘要 III
目錄 V
圖目錄 VIII
表目錄 IX
縮寫對照表 X
第一章 緒論 1
1-1 香菸引起的慢性阻塞性肺病(Chronic obstructive pulmonary disease, COPD) 1
1-1-1 慢性阻塞性肺病(COPD) 1
1-1-2 香菸煙霧 (Cigarette smoke, CS) 1
1-1-3 上皮細胞與巨噬細胞在COPD之角色 2
1月2日 電子煙 (Electronic cigarette) 3
1-2-1 電子煙的主要成分與潛在危害 3
1-2-2 電子煙霧造成的急性肺損傷 5
1-2-3 電子煙霧造成的慢性肺發炎 5
1-3 高遷移率族蛋白1 (High mobility group box 1, HMGB1) 6
1-3-1 HMGB1的功能 6
1-3-2 HMGB1與慢性阻塞性肺病(COPD)之關聯 6
1-3-3 HMGB1與nicotine之關聯 7
1月4日 自噬作用(Autophagy) 8
1-4-1 自噬作用與COPD之關聯 8
1-4-2 自噬作用與HMGB1之關聯 8
1-4-3 自噬作用與nicotine之關聯 9
1月5日 研究目的 9
第二章 材料與研究方法 10
2月1日 實驗儀器 10
2月2日 實驗材料 11
2002/2/1 細胞株 11
2002/2/2 實驗藥品與材料試劑 11
2月3日 實驗方法 12
2002/3/1 細胞培養基與緩衝溶液之配製 12
2002/3/2 水性氣溶膠提取物(Aqueous aerosol extracts, Aae)之製備 14
2002/3/3 細胞培養 (Cell culture) 15
2002/3/4 THP-1 巨噬細胞之分化 15
2002/3/5 細胞存活分析 (MTT assay) 15
2002/3/6 西方墨點法 (Western blot) 16
2002/3/7 統計檢定 19
第三章 實驗結果 21
3月1日 EVE誘發A549上皮細胞毒性和HMGB1釋放 21
3月2日 EVE誘發THP-1巨噬細胞毒性、HMGB1釋放量增加、細胞內HMGB1和LC3B蛋白表現變化 22
3月3日 尼古丁(Nicotine)促進THP-1巨噬細胞HMGB1釋放、細胞HMGB1和LC3B蛋白表現量上升 24
3月4日 保濕劑、電子煙裝置和調味劑對THP-1巨噬細胞毒性的影響 25
第四章 討論 38
4月1日 上皮細胞和巨噬細胞的HMGB1大量釋放可能參與香菸煙霧和電子煙霧引起的肺損傷 38
4月2日 巨噬細胞的自噬作用可能涉及香菸煙霧和電子煙霧造成的肺損傷 39
4月3日 尼古丁可能為引起細胞毒性、HMGB1大量釋放和自噬作用的物質之一 40
4月4日 電子煙的組成對細胞毒性的影響 41
第五章 結論與未來展望 45
參考文獻 46

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