氣喘 (Asthma) 是一種肺部慢性發炎及支氣管過度反應的疾病，為最常見的慢性非傳染性疾病之一。接觸過敏原後會引起發炎細胞浸潤、支氣管收縮和肺部發炎，導致患者出現喘息、胸悶或咳嗽等症狀。目前在氣喘的治療上依其作用可分為控制藥物及緩解藥物，但這些藥物多具有副作用且必須長期使用才能有效地控制氣喘症狀。益生菌 (Probiotics) 能夠定殖於人類胃腸道中，屬於非病性原微生物，通過各種機制發揮其有益作用，包括降低腸道 pH 值、減少病原性微生物的定殖和入侵以及改變宿主免疫反應。本研究使用植物乳桿菌 (Lactobacillus plantarum)，以活體益生菌、熱裂解益生菌及益生菌上清液作為樣品，探討三種益生菌樣品改善氣喘小鼠模型中的過敏作用。細胞實驗方面，以脫顆粒劑化合物 48/80 誘導小鼠肥大細胞株 P815 模擬過敏情形，但益生菌樣品對於抑制脫顆粒作用並沒有顯著效果，顯示植物乳桿菌無法直接作用於細胞改善過敏反應﹔動物實驗方面，利用卵清蛋白 (Ovalbumin, OVA) 誘導 BALB/c 小鼠產生氣喘，並以鼻腔給予及管餵方式探討三種益生菌樣品改善症狀的效果。小鼠經 OVA 刺激後，增加了 Th2 細胞的分化，導致 Th1/Th2 免疫反應失衡，進而吸引促發炎細胞聚集於肺部組織，導致肺部發炎及腫脹﹔Treg 細胞的減少同樣破壞了 Treg/Th17 之間的細胞平衡，促使黏液在肺組織中增生，使氣喘患者出現氣道重塑等病理特徵。給予三種益生菌樣品後，無論是鼻腔給予組或是管餵組，三種益生菌樣品均可降低血清及支氣管沖提液中 IgE 及 IL-4 的表現量，減少促發炎物質的釋放來緩解發炎反應，並且提高脾臟組織中 Treg 細胞的表達來抑制促發炎激素 IL-17 的分泌，調節Treg/Th17 細胞激素的平衡，緩解肺組織中的黏液分泌及纖維化，同時提高 IFN-γ 的分泌抑制 Th2 細胞激素，藉此改善過度的發炎反應及氣道高反應性。在管餵組別中，上清液組比起另外兩個組別更能有效減緩發炎反應﹔鼻腔組別中，熱滅活益生菌組比起另外兩個組別更能有效減緩發炎反應。植物乳桿菌具有改善過敏症狀的潛力，期望可以輔助在氣喘上的治療，為後續的研究提供新的方向。

Asthma is a chronic inflammation of the lungs and bronchial overreaction, and is one of the most common chronic non-communicable diseases. Allergen exposure can cause inflammatory cell infiltration, bronchoconstriction, and lung inflammation, leading to symptoms such as wheezing, chest tightness, or coughing. At present, the treatment of asthma can be divided into control drugs and relief drugs according to their functions, but most of these drugs have side effects and must be used for a long time to effectively control the symptoms of asthma. Probiotics are non-pathogenic microorganisms that colonize the human gastrointestinal tract and exert their beneficial effects through a variety of mechanisms, including lowering intestinal pH, reducing colonization and invasion by pathogenic microorganisms, and altering the host immune response. In this study, Lactobacillus plantarum was used, and live probiotics, heat killed probiotics, and probiotic supernatants were used as samples to investigate the allergy-improving effects of three probiotic samples in a mouse model of asthma. In cell experiments, the mouse mast cell line P815 was induced with degranulation compound 48/80 to simulate allergic conditions, but the probiotic samples had no significant effect on inhibiting degranulation, indicating that Lactobacillus plantarum could not directly act on cells to improve allergic reactions; In terms of animal experiments, Ovalbumin (OVA) was used to induce asthma in BALB/c mice. OVA stimulation in mice increases the differentiation of Th2 cells, resulting in an imbalance of Th1/Th2 immune responses, which in turn attracts pro-inflammatory cells to accumulate in lung tissue, resulting in lung inflammation and swelling; the reduction of Treg cells also destroys Treg/Th17 The balance of cells between them promotes the proliferation of mucus in the lung tissue and causes pathological features such as airway remodeling in patients with asthma. After administration of three probiotic samples, all three probiotic samples can reduce the expression of IgE and IL-4 in serum and bronchial lavage fluid, reduce the release of pro-inflammatory substances to relieve inflammation, and increase the expression of Treg cells in spleen tissue. To inhibit the secretion of pro-inflammatory hormone IL-17, regulate the balance of Treg/Th17 cytokines, relieve mucus secretion and fibrosis in lung tissue, and increase the secretion of IFN-γ to inhibit Th2 cytokines, thereby improving excessive inflammatory response and airway hyperresponsiveness. Lactobacillus plantarum has the potential to improve allergic symptoms and is expected to assist in the treatment of asthma, providing new directions for follow-up research.

目錄
摘要 I
Abstract I
圖目錄 IV
前言 1
第一章、 文獻回顧 2
一、 氣喘 (Asthma) 2
1. 氣喘之介紹 2
2. 氣喘之流行病學 2
3. 氣喘之類型 3
3-1. 外因性氣喘 (Extrinsic asthma) 3
3-2. 內因性氣喘 (Intrinsic asthma) 3
4. 氣喘之臨床病徵 3
4-1. 氣道高反應性 (Airway hyperresponsiveness, AHR) 4
4-2. 氣道重塑 (Airway remodeling) 4
5. 過敏反應 (Hypersensitivity reactions) 4
5-1. 第一型過敏反應 (Type I hypersensitivity reactions) 5
6. 已知氣喘機制 5
6-1. Th1 與 Th2 細胞 5
6-2. Th17 與Treg 細胞 5
7. 氣喘相關研究之小鼠動物模式 6
7-1. 卵清蛋白 (Ovalbumin, OVA) 6
8. 目前對氣喘上的治療及因應對策 6
二、 肥大細胞 7
1. 脫顆粒作用 (Degranulation) 7
2. 化合物 48/80 (Compound 48/80) 7
三、 益生菌 (PROBIOTICS) 8
1. 乳酸菌 (Lactic acid bacteria) 8
2. 植物乳桿菌 (Lactobacillus plantarum) 9
第二章、 實驗設計流程 10
一、 樣品製備 10
二、 細胞實驗 10
三、 動物實驗 11
1. 日程與分組 11
1-1. 管餵組 11
1-2. 鼻內注射組 12
2. 臟器與分析 12
第三章、 實驗材料與方法 13
一、 實驗材料 13
1. 樣品原料 13
2. 細胞株 13
3. 細胞培養之培養基 13
4. 細胞存活率試劑 13
5. P815 脫顆粒誘導試劑 13
6. 實驗動物 13
7. 動物實驗誘導 14
8. RNA 萃取套組 14
9. 反轉錄反應試劑 14
10. 即時定量聚合酶鏈鎖反應試劑 (Real-time PCR) 14
11. 酵素連結免疫吸附法 15
12. 組織切片 15
二、 儀器設備 15
三、 實驗方法 16
1. 實驗樣品製備 16
2. 細胞實驗 (In vitro) 16
2-1. 細胞培養 (Cell culture) 16
2-2. 細胞液之保存 16
2-3. 細胞液之活化 16
2-4. 細胞毒性測試 (Cytotoxicity test) 17
2-5. 肥大細胞脫顆粒試驗 17
2-6. 酵素連結免疫吸附分析法 (Enzyme-linked immunoadsorbent assay, ELISA) 17
3. 動物實驗 (In vivo) 18
3-1. 過敏性氣喘小鼠動物模式 18
3-2. 血液分析 18
3-3. 支氣管沖提液 (Bronchoalveolar lavage fluid, BALF) 分析 18
3-4. 分析組織中細胞激素之 mRNA 表現量 19
3-4-1. 抽取組織 total RNA 19
3-4-2. 反轉錄反應 (Reverse transcription, RT) 19
3-4-3. 即時聚合酶連鎖反應 (Real-time polymerase chain reaction) 19
3-5. 組織病理學切片與染色 20
3-5-1. 石蠟切片 20
3-5-2. 蘇木素-伊紅染色 (Hematoxylin and eosin stain, H&E stain) 20
3-5-3. 過碘酸席夫法 (Periodic Acid-Schiff, PAS) 20
4. 分析組織中免疫細胞表現量 20
5. 統計分析 21
第四章、 結果 22
一、 植物乳桿菌對於 P815 肥大細胞之影響 22
1. 植物乳桿菌對 P815 細胞之細胞毒性 22
2. 植物乳桿菌對 Compound 48/80 誘導 P815 細胞之脫顆粒效果 22
2-1. 細胞型態與脫顆粒情形 22
二、 植物乳桿菌對過敏性氣喘小鼠之動物模式探討 22
1. 建立過敏性氣喘小鼠之動物模式 22
2. 每日體重紀錄 23
3. 組織器官分析 23
3-1. 肺臟組織重量分析 23
3-2. 脾臟組織重量分析 23
4. 發炎細胞計數 24
5. 血清及支氣管肺泡沖提液中白介素-4 及免疫球蛋白 E 分析 24
5-1. 血清 24
5-2. 支氣管肺泡沖提液 25
6. 肺組織細胞激素表達 26
6-1. 管餵組 26
6-2. 鼻腔給予組 27
7. 脾臟組織 Treg 細胞表達 27
8. 肺部組織切片 28
8-1. 蘇木素-伊紅染色 (Hematoxylin and eosin stain, H&E stain) 28
8-2. 過碘酸席夫法 (Periodic Acid-Schiff, PAS) 28
第五章、 討論 29
一、 植物乳桿菌對於 P815 肥大細胞之影響 29
二、 植物乳桿菌於動物模式下改善氣喘相關症狀 30
第六章、 結論 33
第七章、 參考文獻 34
第八章、 圖 43


圖目錄
Figure 1. Cytotoxicity of L. plantarum on P815 mast cells. P815 mast cells were treated with (A) heat killed probiotics and (B) supernatant. 43
Figure 2. The observation of P815 mast cells induced with compound 48/80 and treatment with each concentration of heat killed (HK) probiotics. 44
Figure 3. The observation of P815 mast cells induced with compound 48/80 and treatment with each concentration of probiotics supernatant (SN). 45
Figure 4. Effect of L. plantarum on organ index of lung tissues in ovalbumin (OVA) induced BALB/c mice by (A) oral gavage and (B) intranasal. 46
Figure 5. Effect of L. plantarum on organ index of spleen tissues in ovalbumin (OVA) induced BALB/c mice by (A) oral gavage and (B) intranasal. 47
Figure 6. Differences in (A) white blood cells, (B) lymphocyte, (C) hemoglobin, (D) intermediate cell, and (E) neutrophil in blood of Balb/c mice by oral gavage. 48
Figure 7. Differences in (A) white blood cells, (B) lymphocyte, (C) hemoglobin, (D) intermediate cell, and (E) neutrophil in blood of Balb/c mice by intranasal. 49
Figure 8. Effect of L. plantarum on IL-4 of ovalbumin (OVA) induced BALB/c mice in serum by (A) oral gavage and (B) intranasal. 50
Figure 9. Effect of L. plantarum on IgE of ovalbumin (OVA) induced BALB/c mice in serum by (A) oral gavage and (B) intranasal. 51
Figure 10. Effect of L. plantarum on IL-4 of ovalbumin (OVA) induced BALB/c mice in BALF by (A) oral gavage and (B) intranasal. 52
Figure 11. Effect of L. plantarum on IgE of ovalbumin (OVA) induced BALB/c mice in BALF by (A) oral gavage and (B) intranasal. 53
Figure 12. Effect of L. plantarum on (A) IL-4, (B) IL-5, (C) IL-13, (D) IFN-γ, and (E) IL-17 expression in lung of ovalbumin (OVA) induced BALB/c mice by oral gavage. 54
Figure 13. Effect of L. plantarum on (A) IL-4, (B) IL-5, (C) IL-13, (D) IFN-γ, and (E) IL-17 expression in lung of ovalbumin (OVA) induced BALB/c mice by intranasal. 55
Figure 14. Flow cytometry analysis of Treg cells in the spleen of OVA-induced mice by oral gavage. 56
Figure 15. Flow cytometry analysis of Treg cells in the spleen of OVA-induced mice by intranasal. 57
Figure 16. Effect of L. plantarum with treatment of oral gavage on inflammatory cell infiltrate in lung of ovalbumin (OVA) induced BALB/c mice by H & E stain. 58
Figure 17. Effect of L. plantarum with treatment of intranasal on inflammatory cell infiltrate in lung of ovalbumin (OVA) induced BALB/c mice by H & E stain. 59
Figure 18. Effect of L. plantarum with treatment of oral gavage on mucus distribution in lung of ovalbumin (OVA) induced BALB/c mice by PAS stain. 60
Figure 19. Effect of L. plantarum with treatment of intranasal on mucus distribution in lung of ovalbumin (OVA) induced BALB/c mice by PAS stain. 61
Figure 20. Main mechanisms of action of L. plantarum. 62

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