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研究生:曹正秋
研究生(外文):Cheng-Chiu Tsao
論文名稱:以α-GalCer誘導小鼠模式探討絨毛膜蛻膜間葉幹細胞在慢性肺疾病中的效果
論文名稱(外文):Study on the Effects of Placenta Choriodecidual-Membrane Derived Mesenchymal Stem Cells on the α-GalCer induced Murine Model of Chronic Lung Disease
指導教授:莊雅惠莊雅惠引用關係
指導教授(外文):Ya-Hui Chuang
口試委員:張淑媛林泰元曹伯年
口試日期:2013-06-28
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學檢驗暨生物技術學研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:72
中文關鍵詞:慢性肺部疾病COPDα-GalCer間葉幹細胞
外文關鍵詞:Chronic Lung DiseaseCOPDα-GalCermesenchymal stem cell
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慢性肺部阻塞性疾病(chronic obstructive pulmonary disease, COPD)為阻塞型肺部疾病,是一種長期、慢性且無法恢復的呼吸道氣流阻塞,導致氣體無法通暢地進出呼吸道,此疾病包含慢性支氣管炎與肺氣腫兩類病徵。近年來此疾病的盛行率和死亡率在全世界都持續上升,故臨床上對於其機制和治療的研究也更為積極。間葉幹細胞(mesenchymal stem cells)已被證明可以調控多種免疫與發炎相關的疾病,也被認為具有治療肺部發炎疾病之潛力。本實驗室先前的研究發現,給予小鼠α-GalCer活化iNKT細胞後會造成肺部急性發炎反應。在此,我們探討重覆給予小鼠α-GalCer是否造成慢性肺部發炎及其病理變化特徵。此外,我們探討由人類胎盤蛻膜分離培養之間葉幹細胞(placenta choriodecidual- membrane derived mesenchymal stem cells; pcMSCs)對α-GalCer引起之慢性呼吸道發炎是否具有免疫調控之功能。我們以α-GalCer活化BALB/c小鼠之iNKT細胞後發現小鼠肺部的細胞激素IFN-γ及 IL-4升高且浸潤細胞亦增加,確認iNKT細胞在肺部發炎疾病之重要性。接著我們以鼻腔注射重複給予小鼠α-GalCer後顯示這些小鼠有較高的支氣管肺泡沖洗液中浸潤的細胞總數、巨噬細胞、淋巴球(T/NK/NKT細胞)、嗜中性球以及CD8 T細胞。肺臟發炎細胞激素IL-6及TNF-α升高。組織病理分析可發現有細胞浸潤以及肺泡破壞之情形、分泌Mucus的細胞表現量增加,collagen的沉積增加。另外Muc5ac、collagen type 3、MMP-12等基因表現在重複給予α-GalCer的小鼠肺臟均顯著上升。這些慢性發炎反應之特徵與人類COPD相似。此外,體外試驗結果顯示pcMSCs會抑制骨髓培養之巨噬細胞分泌IL-6、TNF-α以及增生的能力。進一步在α-GalCer引起之COPD小鼠模式中給予pcMSCs,結果顯示,與對照組相比,COPD小鼠在接受pcMSCs後支氣管肺泡沖洗液中浸潤的細胞總數及巨噬細胞數均上升,而CD8 T細胞則沒有差異。在組織病理部分,小鼠組織中浸潤的細胞與肺泡破壞程度無顯著差異;然而我們卻發現小鼠在接受pcMSCs後支氣管肺泡沖洗液中CD4 T細胞增加,值得注意的是肺臟發炎細胞激素IL-6及TNF-α顯著降低,組織中黏液細胞減少,此外Muc5Ac表現亦顯著降低。綜合以上實驗,我們以重覆鼻腔注射給予α-GalCer可建立與人類COPD特徵相似之小鼠。另外我們證明pcMSCs可降低COPD的黏液分泌及細胞激素的表現。

Chronic obstructive pulmonary disease (COPD) is characterized by long-term, chronic and irrevrseble airflow limitation. It includes chronic bronchitis and alveolar destruction (emphysema). The mortality and prevalence rate of COPD increases recently and therapeutic approaches are required. Recent studies, which have revealed that mesenchymal stem cells (MSC) contribute to immunomodulation of inflammation disease, are potential therapeutic applications in airway inflammation diseases. Our previous studies demonstrated that activation of iNKT cells by intranasal injection of α-GalCer induced acute airway inflammation. In this study, we investigated whether chronic airway inflammation could be induced in mice by repeated intranasal injection of α-GalCer and we characterized the pathological changes of these mice. We further investigated the effects of placenta choriodecidual-membrane derived mesenchymal stem cells (pcMSCs) on chronic airway inflammation. Our results demonstrated that intranasal administration of α-GalCer induced the activation of iNKT cells by secreting cytokine such as interferon-γ (IFN-γ) and interleukin (IL)–4 and recruited cell infiltration to lung. These results confirmed the importance of activation of iNKT cells in the airway inflammation. By repeated intranasal injection of α-GalCer to mice, we found that increased airway inflammation, including increase in total BALF cell counts, macrophages, lymphocytes (T/NK/NKT cells), neutrophils and CD8 T cells were observed in α-GalCer injected mice. In addition, inflammatory cytokine such as IL-6 and TNF-α in lung increased. In the histopathological study, cell infiltration, alveolar destruction, mucus production and collagen deposition were found in repeatedly intranasal α-GalCer injected mice. Moreover, the level of Muc5ac, collagen type 3 and MMP-12 were also significantly increased. All of these features are similar to human COPD. Next, we showed that pcMSCs could inhibit the IL-6 and TNF-α production and proliferation of macrophage in vitro. We then investigated the effects of pcMSCs using the murine model of COPD. Compared with the control group, BALF total cells and macrophages increased. There was no difference in the number of CD8 T cells while increased CD4 T cells were found. No difference levels of cell infiltration and alveolar destruction were observed in these two groups. Of note, IL-6 and TNF-α production as well as mucus production in tissues and Muc5Ac expression were significantly decreased in COPD mice receiving pcMSCs. In conclusion, we set up a mouse model of COPD by repeated injection of α-GalCer and we demonstrated that pcMSCs may decrease the mucus production and proinflammatory cytokine production of COPD.

致謝 i
中文摘要 ii
Abstract iv
縮寫對照表 vi
第一章 研究背景 1
1.1 肺部慢性發炎疾病-阻塞性肺部疾病 1
1.2 氣喘 (Asthma) 1
1.2.1 非過敏性氣喘 (non-allergic asthma) 2
1.3 慢性肺部阻塞性疾病 (Chronic Obstructive Pulmonary Disease,COPD) 2
1.3.1 肺氣腫 (Emphysema) 3
1.3.2 黏液過度分泌 (Mucus hypersecretion) 4
1.3.3 肺部纖維化 (Lung fibrosis) 4
1.3.4 慢性肺部阻塞性疾病與發炎反應 4
1.3.5 巨噬細胞 (Macrophages)與慢性肺部發炎反應之關係 5
1.3.6 嗜中性球 (Nertrophils) 與慢性肺部發炎反應之關係 5
1.3.7 T淋巴球 (T lymphocyte) 與慢性肺部發炎反應之關係 6
1.4 自然殺手T 細胞 (Nature Killer T cells;NKT cells) 6
1.4.1 NKT細胞之分類 7
1.4.2 iNKT細胞之抗原辨識與直接活化 7
1.4.3 iNKT細胞與慢性肺部發炎反應之關係 8
1.5 間葉幹細胞 (mesenchymal stem cells) 8
1.5.1胎盤絨毛膜蛻膜間葉幹細胞 (Placenta choriodecidual-membrane derived mesenchymal stem cells) 9
1.5.2 間葉幹細胞與慢性肺部疾病 10
1.6 研究目的 10
第二章 實驗材料與方法 11
2.1 實驗用小鼠 11
2.2 α-galactosylceramide (α-GalCer)活化NKT細胞引發肺部發炎小鼠模式之建立 11
2.2.1 以α-GalCer活化NKT細胞引發之肺部急性發炎反應動物模式 11
2.2.2 重複給予α-GalCer引發肺部慢性發炎反應之小鼠模式之建立 11
2.3 α-galactosylceramide (α-GalCer)之給予 12
2.4 小鼠支氣管肺泡沖洗液(bronchoalveolar lavage fluid;BALF)之收集與處理 12
2.5 小鼠支氣管肺泡沖洗液之細胞離心與染色 12
2.6 小鼠支氣管肺泡沖洗液之細胞分類 13
2.7 小鼠支氣管肺泡沖洗液淋巴球細胞之組成 13
2.8 ELISA偵測細胞激素(IL-4、IFN-γ、IL-6、TNF-α) 14
2.9 小鼠肺臟灌流與病理切片之製作 14
2.10 石蠟組織切片 15
2.11 Hematoxylin-eosin (H&E)染色 15
2.12 Periodic acid-Schiff (PAS)染色 16
2.13 Massion’s Trichrome stain 17
2.14 計算肺部組織中肺泡壁之間距 17
2.15 肺臟組織RNA之萃取 17
2.16 利用RNA反轉錄成cDNA之過程 18
2.17 以即時定量反轉錄聚合酶連鎖反應偵測相關蛋白之mRNA的表現量(Muc5ac、α-SMA、collagen type 1、collagen type 3、細胞激素(IL-6、TNF-α)、MMP-12。 18
2.18 由骨髓衍生之巨噬細胞 (Bone marrow derived Macrophage, BMMs)分離及培養 19
2.19 骨髓衍生之巨噬細胞與絨毛膜蛻膜間葉幹細胞(pcMSCs)共同培養 19
2.20 骨髓衍生之巨噬細胞增生試驗 (3H-thymidin assay) 20
2.21 絨毛膜蛻膜間葉幹細胞(pcMSCs)在COPD小鼠之效果 20
2.22 繪圖與統計分析 20
第三章 實驗結果 21
3.1以α-GalCer活化iNKT細胞引發之肺部急性發炎反應 21
3.1.1 小鼠給予α-GalCer活化iNKT細胞後,支氣管肺泡沖洗液中可測得大量表現的IL-4以及IFN-γ。 21
3.1.2 小鼠給予α-GalCer活化iNKT細胞後,在不同時間點犧牲,肺臟內浸潤細胞數與各種浸潤細胞皆有明顯上升。 21
3.2 以重複給予小鼠α-GalCer活化NKT細胞進而引發肺部慢性發炎反應。 22
3.2.1 重複給予小鼠α-GalCer於肺臟病理組織切片發現有淋巴細胞之浸潤。 22
3.2.2重複給予小鼠α-GalCer後造成肺部發炎細胞之浸潤,T淋巴球組成變化,以及NKT表現上升。 22
3.2.3 重複給予小鼠α-GalCer後,肺部細胞激素IL-6以及TNF-α皆有顯著上升。 23
3.2.4重複給予小鼠α-GalCer後,於肺部組織特殊染色(PAS stain)中發PAS+cells的表現增加以及Muc5ac基因表現上升。 23
3.2.5重複給予小鼠α-GalCer後,於小鼠肺部病理組織發現有破壞之情形,以及MMP-12(造成肺氣腫相關的基因)也有顯著上升。 24
3.2.6重複給予小鼠α-GalCer後,於肺部組織特殊染色(Trichrome stain)發現有些微collagen的沉積以及纖維化蛋白基因 collagen type 3的上升。 25
3.3 體外試驗證明絨毛膜蛻膜間葉幹細胞(pcMSCs)造成骨髓巨噬細胞(BM-Macrophages)分泌IL-6以及TNF-α及細胞增生的能力下降。 26
3.4重複給予小鼠α-GalCer引起之COPD中給予絨毛膜蛻膜間葉幹細胞(pcMSCs)之影響。 26
3.4.1 COPD小鼠在接受pcMSCs後,病理組織有淋巴球的浸潤,而肺部支氣管沖洗液中發炎細胞浸潤增加,其中以巨噬細胞最為顯著。 27
3.4.2 COPD小鼠在接受pcMSCs後,T淋巴球組成以及CD8 T細胞無顯著差異,CD4 T細胞則有較為顯著的上升。 27
3.4.3 COPD小鼠在接受pcMSCs後,TNF-α以及collagen type 3皆無顯著差異,IL-6的表現則有下降。 28
3.4.4 COPD小鼠在接受pcMSCs後,於肺部組織特殊染色(PAS stain)中發現PAS+ cells下降以及Muc5Ac基因表現顯著下降。 28
3.4.5 COPD小鼠在接受pcMSCs後,於小鼠肺部病理組織發現仍有破壞之情形,以及MMP-12(造成肺氣腫相關的基因)也無顯著變化。 29
第四章 討論 30
附表 35
附圖 39
參考文獻 58
附錄 69



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