異位性皮膚炎 (Atopic dermatitis, AD) 為皮膚過敏性疾病，全球約有五分之一的人口受到該病的影響，嬰幼兒及青少年為主要患者。一般症狀為皮膚發癢、紅腫及龜裂，長期搔抓易使病灶處惡化。目前治療 AD 多使用類固醇藥物，但長期使用易有副作用。益生菌具有改變腸道菌相的益處，能調節免疫功能，降低發炎因子產生。本研究利用化合物 48/80 (Compound 48/80) 誘導之 P815 肥大細胞與益生菌配方 (Probiotics formula, PF) 共培養後其脫顆粒現象及以 2,4-二硝基氯苯 (2,4-Dinitrochlorobenzene; DNCB) 誘導之 AD 小鼠在預防或治療食用 PF 後，免疫系統中第一型輔助型 T 細胞 (Helper T cell type 1; Th1) 及 Th2 調節情形與改善 AD 症狀之成效。細胞實驗上，PF 能顯著地減少介白素-4 (Interluekin-4; IL-4) 和組織胺 (Histamine) 產生及提高干擾素-γ (Interferon-γ; IFN-γ) 表現量。動物實驗上，預防試驗中，將 PF 餵食於小鼠，一周後進行誘導。皮膚炎評分結果顯示 PF 可有效的改善 AD 發炎症狀。於組織切片結果表示 PF 能降低嗜酸性顆粒球及肥大細胞於皮膚組織中的浸潤。由細胞因子測定結果發現 Th2 中的過敏主要因子免疫球蛋白 E (Immunoglobin E; IgE) 及腫瘤壞死因子-α (Tumor necrosis factor-α; TNF-α) 皆有顯著的降低，而 Th1 中的 IFN-γ 則有明顯的提高。由於在預防上有良好的效果，因此後續則進行治療試驗。治療試驗中，先將小鼠誘導出異位性皮膚炎後開始餵食 PF。動物觀察評分結果顯示 PF 可顯著降低 AD 症狀，且也可減少嗜酸性顆粒球及肥大細胞在皮膚組織的浸潤。測量血清細胞因子之結果，PF 能降低 IgE 與 TNF-α 濃度，提升 IFN-γ 含量。綜合上述結果，PF 在細胞及動物實驗上皆可提高 IFN-γ 表現量，細胞實驗能減少 IL-4 與 histamine 表現，而動物實驗上則能降低 IgE 及 TNF-α 表現，但預防較治療效果尤佳。期望在未來能了解益生菌對於針對異位性皮膚炎更深入之機制及有效的生理活性成分。

Atopic dermatitis (AD) is an allergic skin disorder. About one-fifth of the world’s population is affected by this disease. Infants, young children and adolescents are the main patients. The general symptoms on skin are itchy, redness, and cracking. Long-term scratching can make the lesional skin worse. Presently, steroid drugs are often used to treat AD, but long-term use tends to have side effects. Probiotics have the benefit of changing the intestinal microflora, regulate immune function, and reduce the production of inflammatory cytokines. This report uses compound 48/80-induced P815 mast cells and probiotics formula (PF) to induce degranulation and DNCB (2,4-Dinitrochlorobenzene) induced AD mice to pre-treat or post-treat with PF. Afterwards, Helper T cell type 1 (Th1) and Th2 regulation in the immune system improve the symptoms of AD. In vitro, PF can significantly reduce interleukin-4 (IL-4) and histamine production and increase IFN-γ performance. In vivo, PF was fed to mice in a prophylactic experiment and induced 1 week later. Animal observation scores showed that PF can effectively improve the symptoms of AD. The result of the histologic section indicated that PF can reduce the infiltration of eosinophils and mast cells in the skin tissue. According to the results of cytokine analysis, the allergic factor, immunoglobin E (IgE), and tumor necrosis factor-α (TNF-α) in Th2 were significantly reduced, while interferon-γ (IFN-γ) in Th1 was significantly decreased. There is an effective improvement. Because of the good results in pre-treatment, follow-up post-treatment were conducted. In the post-treatment, mice were initially induced atopic dermatitis and then fed PF. Animal observation scores showed that PF can significantly reduce the symptoms of AD, and can also reduce the infiltration of eosinophils and mast cells in the skin tissue. As a result of measuring serum cytokines, PF can reduce the IgE, TNF-α concentration and increase IFN-γ concentration. In conclusion, PF can increase the expression of IFN-γ in both cell and animal experiments. In vitro can reduce the expression of IL-4 and histamine, while in vivo can reduce the performance of IgE and TNF-α. In vivo, pre-treatment is more effective than post-treatment. It is expected that in the future, probiotics formula will be understood to have a deeper mechanism for atopic dermatitis and an effective physiologically active ingredient.

摘要.....................................................I
Abstract................................................II
圖次...................................................VII
第一章 前言...............................................1
第二章 文獻回顧...........................................2
一、皮膚構造及功能.........................................2
1. 表皮 (Epidermis)......................................2
1-1 角質層 (Stratum corneum).............................2
1-2 透明層 (Stratum lucidum).............................2
1-3 顆粒層 (Stratum granulosum)..........................2
1-4 棘狀層 (Stratum spinosum)............................2
1-5 基底層 (Stratum).....................................2
2. 基底膜帶..............................................3
3. 真皮層 (Dermis).......................................3
3-1. 乳頭層 (Papillary layer)............................3
3-2. 網狀層 (Reticular layer)............................3
4. 上皮附屬器官...........................................3
4-1. 毛髮 (Hair).........................................3
4-2. 汗腺 (Sweat glands).................................3
4-3. 皮脂腺 (Subaceous glands)...........................3
二、異位性皮膚炎 (Atopic dermatitis)......................3
1. 異位性皮膚炎簡介.......................................3
1-1 急性期異位性皮膚炎 (Acute phase).......................4
1-2 慢性期異位性皮膚炎 (Chronic phase).....................4
1-3 異位性皮膚炎之正確觀念.................................4
2. 異位性皮膚炎之病因......................................4
3. 異位性皮膚炎之診斷......................................5
4. 異位性皮膚炎之治療......................................5
4-1 皮質類固醇 (Corticosteroids)..........................5
4-2 抗組織胺 (Anti-histamine).............................6
三、肥大細胞脫顆粒作用 (Degranulation).....................6
四、化合物 48/80 (Compound 48/80).........................7
五、誘導異位性皮膚炎之動物模式..............................7
1. 經表皮致敏誘發異位性皮膚炎模型...........................7
1-1 卵白蛋白 (Ovalbumin, OVA).............................7
1-2 居家塵蟎 (House dust mite, HDM) 過敏原................7
1-3 半抗原 (Hapten)......................................7
1-4 超級抗原 (Superantigen)..............................8
1-5 食品過敏小鼠模型......................................8
2. 基因工程小鼠之異位性皮膚炎模型..........................8
3. 自發性異位性皮膚炎小鼠模型..............................8
六、益生菌 (Probiotics)...................................9
1. Lactobacillus paracasei...............................9
2. Lactobacillus fermentum..............................10
3. Lactobacillus acidophilus............................10
4. Lactobacillus rhamnosus..............................10
第三章 實驗設計流程.......................................11
一、益生菌配方對於抑制肥大細胞脫顆粒之效果..................11
二、益生菌配方對於異位性皮膚炎症狀之改善效果................11
第四章 實驗材料與方法.....................................12
一、實驗材料.............................................12
1. 樣品原料..............................................12
2. 細胞株................................................12
3. 細胞培養之培養基......................................12
4. 細胞存活率試劑........................................12
5. P815 脫顆粒誘導試劑...................................12
6. 實驗動物..............................................12
7. 動物實驗誘導..........................................12
8. 組織切片..............................................13
9. 酵素連結免疫吸附分析法.................................13
二、儀器設備.............................................13
三、實驗方法.............................................14
1. 細胞實驗 (In vitro)...................................14
1-1 細胞培養.............................................14
1-2 細胞保存.............................................14
1-3 細胞活化.............................................14
1-4 細胞毒性測試 (Cytotoxicity test).....................14
1-5 肥大細胞脫顆粒測定 (Mast cell degranulation test).....14
1-6 酵素連結免疫吸附分析法 (Enzyme-linked immunoadsorbent assay, ELISA)...........................................15
1-7 甲苯胺藍染色 (Toluidine blue stain, TB stain)........15
2. 動物實驗 (In vivo)....................................15
2-1 異位性皮膚炎小鼠動物模式..............................15
2-1-1 預防組.............................................15
2-1-2 治療組.............................................15
2-1-3 皮膚炎症狀評估.....................................16
2-1-4 組織病理切片.......................................16
2-1-5 酵素連結免疫吸附分析法 (Enzyme-linked immunoadsorbent assay, ELISA)...........................................16
2-1-6 血液分析...........................................17
3. 統計分析..............................................17
第五章 結果..............................................18
一、Compound 48/80 誘導 P815 脫顆粒之效果.................18
二、Probiotics formula 減少 P815 脫顆粒之效果.............18
1. 細胞型態及脫顆粒情形...................................18
2. 培養液中細胞因子分析...................................18
2-1. 介白素-4 (Interluekin-4, IL-4)......................18
2-2. 組織胺 (Histamine)..................................18
2-3. 干擾素-γ (Interferon-γ, IFN-γ)......................19
三、建立異位性皮膚炎小鼠之模式.............................19
四、Probiotics formula 預防異位性皮膚炎之效果.............19
1. 皮膚炎評分............................................19
2. 皮膚組織切片..........................................20
3. 血清中細胞因子分析.....................................20
3-1 免疫球蛋白 E (Immunoglobin E, IgE)...................20
3-2 腫瘤壞死因子-α (Tumor necrosis factor-α, TNF-α)......20
3-3 干擾素-γ (Interferon-γ, IFN-γ).......................20
五、Probiotics formula 治療異位性皮膚炎之效果.............20
1. 皮膚炎評分............................................20
2. 皮膚組織切片..........................................21
3. 血清中細胞因子分析.....................................21
3-1 免疫球蛋白 E (Immunoglobin E, IgE)...................21
3-2 腫瘤壞死因子-α (Tumor necrosis factor-α, TNF-α)......21
3-3 干擾素-γ (Interferon-γ, IFN-γ).......................21
第六章 討論..............................................22
一、Probiotics formula 抑制以 Compound 48/80 誘導之 P815 脫顆粒效果.................................................22
1. Compound 48/80 對於刺激 P815 脫顆粒作用................22
2. Probiotics formula 減輕 P815 脫顆粒作用...............22
二、Probiotics formula 改善以 DNCB 誘導之異位性皮膚炎小鼠之效果......................................................23
1. 皮膚炎狀態評分........................................23
1-1. 馴養適應期..........................................23
1-2. 預防對於改善異位性皮膚炎症狀評分之情形................23
1-3. 治療對於改善異位性皮膚炎症狀評分之情形................23
2. 皮膚組織切片 H&E 染色後顆粒球浸潤現象...................24
3. 皮膚組織切片 TB 染色後肥大細胞浸潤現象..................24
4. 血清中抗體與細胞因子分析...............................24
第七章 結論..............................................26
參考文獻.................................................27

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