臺灣博碩士論文加值系統

肺臟纖維化是一種漸進且不可逆的病理過程，肺部受損導致肺泡細胞死亡、減少，肺泡組織間被纖維化組織取代。至今臨床上，沒有藥物能夠有效治療肺臟纖維化，僅能降低患者的不適感或延緩病情惡化。因此，尋求能夠逆轉治療肺部纖維化的方法是至關重要的議題。本實驗先透過注射博來黴素(Bleomycin，簡稱 BLM) 造成大白鼠左肺纖維化之後，才開始給予不同分子量玻尿酸。探討不同分子量玻尿酸治療肺臟纖維化的效果與差異。
經由大白鼠左支氣管給予5 mg BLM，造成左肺產生穩定、且嚴重的肺臟纖維化，於傷害後的第21天起，由大白鼠左支氣管，分別給予低分子量、中分子量、高分子量、以及綜合分子量玻尿酸，在第49天犧牲，觀察其肺臟功能以及肺臟病理變化的情形。
給予不同分子量的玻尿酸，均能提升肺纖維化病鼠動脈血之含氧飽和度。其中，僅有給予綜合分子量玻尿酸之大白鼠，其動脈血中的氧分壓能明顯上升、二氧化碳分壓能快速下降、並且呼吸急促的現象能顯著的降低。
另外，以電腦斷層影像連續追蹤大白鼠肺泡的變化情形。結果顯示，給予綜合分子量玻尿酸能促進肺纖維化病鼠肺泡的增多。在實驗的第49天犧牲大白鼠，由肺臟巨觀顯示，BLM傷害後之肺纖維化病鼠，左肺明顯的萎縮；給予綜合分子量玻尿酸，可以提升左肺肺泡體積，與改善肺泡結構。
進一步，給予中分子、高分子、與綜合分子量玻尿酸都可以降低左肺組織間之膠原蛋白沉積，並且，左肺中巨噬細胞細胞質內具有顆粒狀之細胞比例也明顯上升。另外，給予高分子、與綜合分子量玻尿酸可以明顯降低α-SMA的表現、和顯著減少肺洗液中之細胞數目。
綜合以上實驗結果，肺臟纖維化病鼠給予綜合分子量玻尿酸能有效提升肺臟功能、改善肺臟組織、並緩解肺臟纖維化。希望對肺纖維化病患能提供另一個可能的治療方法。

Pulmonary fibrosis (PF) is an irreversible and progressing process characterized by the gradual reduction of alveolar epitheliums and replacement of alveolar tissue with fibrotic tissue. To date, there are no effective treatments for PF clinically but only for relieving symptoms or slowing down the disease progression. Therefore, it is a critical issue to identify therapies that are able to reverse PF. In this study, we investigated the therapeutic effect of administrating low, medium, high, or mixed molecular weight of hyaluronan (HA) on bleomycin (BLM) induced PF rats.
Rats were injected with 5 mg of BLM through the left bronchus, causing steady and severe PF in the left lung. On day 21 after the BLM injection, low, medium, high, or mixed molecular weight HA was administered intratracheally to the left lung. Lung function and pathology were observed until day 49.
Our study demonstrated that the administration of different molecular weight HA resulted in the enhancement of blood oxygen concentration. However, the increase in arterial oxygen pressure and the decrease in arterial carbon dioxide pressure and respiratory rate were only observed with the administration of mixed molecular weight HA.
Moreover, the results of lung computed tomography showed that the administration of mixed molecular weight HA increased the number of alveoli in PF rats. Morphologically, the administration of mixed molecular weight HA promoted lung volume and improved alveolar structure in PF rats.
The amelioration of collagen deposition and the increased population of macrophages with particles were observed with the administration of medium, high, and mixed molecular weight HA. Furthermore, the administration of high and mixed molecular weight HA decreased inflammation and the activity of myofibroblasts.
Based on our observations, the administration of mixed molecular weight HA performed better than single molecular weight HA in promoting lung function, improving alveolar tissue, and alleviating PF.

目錄
中文摘要i
英文摘要iii
目錄v
圖目錄ix
表目錄xi
第一章 緒論1
1.1 肺臟纖維化的病理發展1
1.2 治療藥物於肺臟纖維化的基礎醫學研究3
1.3 臍帶間質幹細胞逆轉修復肺臟纖維化4
1.4 玻尿酸 (Hyaluronic acid，簡稱HA)5
1.5 不同分子量玻尿酸對身體器官的醫學研究7
1.6 玻尿酸於肺臟的基礎醫學研究8
第二章 研究目的11
第三章 材料與方法12
3.1 實驗動物12
3.2 撲類惡/博來黴素注射劑12
3.3 左側單肺纖維化動物模式的建立12
3.4玻尿酸溶液配製13
3.5 實驗分組13
3.6 實驗動物肺功能檢測15
3.6.1 動脈血氧飽和度的測定15
3.6.2動脈血的氧分壓與二氧化碳分壓的檢測15
3.6.3 呼吸頻率的測定16
3.7 小動物電腦斷層造影 (Micro Computed Tomography，簡稱CT)16
3.7.1 電腦斷層造影16
3.7.2 電腦斷層造影3D圖檔的建立與體積計算17
3.8 實驗動物犧牲和灌流固定17
3.9 組織的石蠟包埋和切片18
3.9.1 組織脫水18
3.9.2 組織浸蠟包埋18
3.9.3 組織切片和取片方式18
3.10 組織化學染色20
3.10.1 蘇木紫-伊紅染色 (Hematoxylin & Eosin stain，H&E Stain)20
3.10.2 組織纖維化染色 (Sirius Red Stain)21
3.10.3 組織免疫染色 (Immunohistochemistry，簡稱IHC)21
3.11 支氣管肺泡沖洗液 (Bronchoalverlar lavage，簡稱 BAL) 細胞計數22
3.12 統計分析23
第四章 結果24
4.1 給予玻尿酸治療，對於肺纖維化病鼠的體重，沒有顯著的影響24
4.2 給予玻尿酸，可增加肺纖維化病鼠的動脈血氧飽和度24
4.3 給予玻尿酸對動脈血氧分壓與二氧化碳分壓的影響26
4.3.1 給予高分子、或綜合分子量玻尿酸，能提升肺纖維化病鼠的動脈血氧分壓26
4.3.2 給予中分子、或綜合分子量玻尿酸，能快速降低動脈血中之二氧化碳分壓26
4.4 給予綜合分子量玻尿酸，能減緩肺纖維化病鼠的呼吸頻率27
4.5 由電腦斷層3D影像顯示，給予綜合分子量玻尿酸，可以促進肺泡的再生28
4.6 由肺臟巨觀顯示，給予綜合分子量玻尿酸，能促進肺纖維化大白鼠左肺體積的增加30
4.7 從蘇木紫-伊紅染色結果顯示，給予綜合分子量玻尿酸，能增加肺纖維化大白鼠的肺臟體積、與改善肺泡結構31
4.8 組織纖維化染色結果顯示，給予中、高、與綜合分子量玻尿酸，能降低肺纖維化病鼠肺臟內膠原蛋白的沉積33
4.9 給予高分子、綜合分子量玻尿酸，能降低肺纖維化病鼠左肺中，肌纖維母細胞的活化34
4.10 給予中、高、或綜合分子量玻尿酸能改變肺纖維化病鼠左肺中的巨噬細胞型態35
4.11 給予高分子量或綜合分子量玻尿酸，減少肺纖維化病鼠左肺支氣管肺泡沖洗液內的細胞數量36
第五章、討論37
5.1 玻尿酸於早期肺臟疾病的治療或預防37
5.2 不同分子量玻尿酸治療急性肺臟損傷可能的機制38
5.2.1 玻尿酸影響發炎反應38
5.2.2 玻尿酸影響巨噬細胞的存活與極化40
5.2.3 玻尿酸影響肺泡上皮細胞的再生42
5.3比較人類臍帶間質幹細胞與玻尿酸於肺臟纖維化的治療45
5.4結論與未來展望47
第六章 參考文獻48
第七章 圖表54

圖目錄
圖一、誘發大白鼠肺纖維化、分別給予不同分子量玻尿酸的實驗流程圖。55
圖二、給予玻尿酸治療，對於肺纖維化病鼠的體重變化，沒有顯著的影響。56
圖三、給予玻尿酸，可增加肺纖維化病鼠的動脈血氧飽和度。57
圖四、給予高分子、或綜合分子量玻尿酸，能提升肺纖維化病鼠的動脈血氧分壓。58
圖五、給予中分子、或綜合分子量玻尿酸，能快速降低動脈血中的二氧化碳分壓。59
圖六、給予綜合分子量玻尿酸，能減緩肺纖維化病鼠的呼吸頻率。60
圖七、肺臟電腦斷層3D模型的建立。62
圖八、由電腦斷層3D影像，呈現肺臟肺泡的變化情形。64
圖九、由電腦斷層3D影像顯示，給予綜合分子量玻尿酸，可以促進肺泡的再生。65
圖十、所有組別的肺泡空間變化。66
圖十一、由肺臟巨觀顯示，給予綜合分子量玻尿酸，能促進肺纖維化大白鼠左肺體積的增加。68
圖十二、左肺石蠟切片、與取片方法。69
圖十三、從HE染色結果顯示，給予綜合分子量玻尿酸，能增加肺纖維化大白鼠的肺臟體積、與改善肺泡結構。71
圖十四、給予中、高、與綜合分子量玻尿酸，能降低肺纖維化病鼠肺臟內膠原蛋白的沉積。73
圖十五、給予高分子、綜合分子量玻尿酸，能降低肺纖維化病鼠左肺中，肌纖維母細胞的活化。74
圖十六、給予中、高、或綜合分子量玻尿酸能改變肺纖維化病鼠左肺中的巨噬細胞型態。75
圖十七、給予高分子量或綜合分子量玻尿酸，減少肺纖維化病鼠左肺支氣管肺泡沖洗液內的細胞數量。77

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