臺灣博碩士論文加值系統

背景：氣喘是一種複雜的慢性呼吸道發炎疾病，具有不同的表現型和嚴重程度，並伴隨有嚴重的健康和經濟負擔。建立氣喘之動物實驗模式可以提供有關氣喘致病機轉和治療信息。雞卵蛋白（OVA）致敏在氣喘模式中有其局限性。此外，我們調查到DerP是家塵蟎之一，更是台灣的常見的主要過敏原。本研究使用DerP建立更貼近臨床的動物致敏模式。益生菌是一種微生物，其可為宿主提供健康益處，調節腸道中的微生物平衡，控制免疫微環境並緩解過敏和發炎。
研究目的：研究OVA和Der pII1-129致敏鼠的免疫系統是否有很多不同。並探討益生菌LGG和LGG結合prednisolone在過敏氣哮喘小鼠模型中對呼吸道發炎的作用。
材料與方法：本研究使用雌性、BALB / c小鼠，進行急性期（28天）和慢性期（76天）的致敏模式，並使用OVA或Der pII1-129作為致敏原。並納入單純口服LGG、口服prednisolone或prednisolone + LGG對動物進行治療。評估呼吸道過度反應（AHR），血清特異性IgE / IgG1 / IgG2a，肺部發炎細胞浸潤和細胞激素的表現。
結果：不僅OVA致敏，而且Der pII1-129致敏均可成功誘導AHR，高表現量IgE以及肺部發炎細胞浸潤等。細胞激素部分，OVA致敏鼠可能具有最高的Th2細胞激素和IL-6表達，而Der pII1-129致敏鼠則是以IL-8，IL-10，IL-13和TGF-β表現量較高。在LGG治療組中，呼吸道發炎、Th1 / Th2細胞激素分泌平衡和肺部發炎細胞浸潤等皆有改善。此外，合併治療組（LGG +prednisolone）對AHR的抑制作用比單一治療組更為顯著。在接受單一治療或合併治療的小鼠中，血清IgE和IgG1表現量均有降低。合併治療組甚至可以比單一治療組有更高的IgG2a表現量。除Th2細胞激素外，合併治療組還抑制了與類固醇阻抗有關的IL-6，IL-8和IL-17。合併治療可顯著減少肺部發炎細胞浸潤並減輕呼吸道發炎。
結論：單純口服益生菌可以改善氣喘的嚴重程度。益生菌合併同糖皮質激素可更提升其抗發言作用，因此對氣喘治療是更有幫助的。用不同的過敏原致敏可能發揮不同的免疫環境。此外，用純化的Derp II1-129進行致敏研究，可提供更貼近人類氣喘的小鼠致敏模式，其可用於探討預防或治療致敏原誘導的呼吸道炎症狀的不同介入策略。

BACKGROUND: Asthma is a complex multifactorial chronic airway inflammatory disease with diverse phenotypes and levels of severity and is associated with significant health and economic burden. The ethical issues associated with the studies in asthmatic patients, required development of animal model of asthma. Animal models of asthma can provide valuable information on several features of asthma pathogenesis and treatment. Ovalbumin (OVA) sensitization has limitations in modelling asthma. Thus, we detected the allergen sensitization used DerP which one of HDMs and common allergen in Taiwan. Probiotics are microorganism which can provide health benefit to host, regulate microbial balance in the intestine, control immune microenvironment and alleviate the condition of allergy and inflammation.
OBJECT：We investigate whether had many different of immune system in OVA and DerPII1-129 sensitization mice. and to explore probiotics-LGG and the combination effects of LGG with prednisolone in controlling airway inflammation in a murine model for allergic asthma.
METHODS: We used OVA or Der p 2-sensitized asthma model in female BALB/c mice during sensitization in acute stage (28 days) and chronic stage (76 days). The animals were only treated with LGG, oral prednisolone or combination treatment with both LGG. Airway hyperresponsiveness, serum specific IgE/ IgG1/ IgG2a, infiltrating inflammatory cells in lung and cytokines in BALF were assessed.
RESULTS：According to the results, not only OVA, but also DerP2 sensitization mice could induce AHR, high levels of IgE, inflammatory cell infiltration in lung and airway inflammation. In cytokines, OVA sensitized mice could induce more higher Th2 cytokines than DerP2 sensitization. Moreover, IL-6, IL-8, IL-10, IL-13 and TGF-b in BALF were express higher in DerP2 sensitization mice than OVA sensitization.
In LGG treated groups were improved airway imflammation, Th1/Th2 cytokines balance and inflammatory cell infiltration in lung. Moreover, the suppression of AHR was more significant in combination therapy groups (LGG+prednisolone) than the single therapy groups. The serum IgE and IgG1 level were both decreased in the mice receiving single therapy or combination therapy. The combination therapy groups could even upregulate serum IgG2a level more than the single therapy groups. Besides Th2 cytokines, combination therapy also inhibits IL-6, IL-8 and IL-17 which are associated with steroid insensitivity. Combination treatment decreased the infiltrating inflammatory cells in the lungs significantly and ameliorated lung inflammation.
CONCLUSIONS：Probiotics only may improve the severity of asthma. And Probiotics may synergize the anti-inflammatory effect of glucocorticoids and thus may be beneficial in the treatment of asthma. Sensitization with different allergens may play different immune environment. Moreover, sensitized with allergen of purified DerPII1-129 offers a more relevant murine model of human allergic asthma and can be suitable for characterizing different intervention strategies to prevent or treat allergen-induced lung inflammation.

目錄
謝誌 ------------------------------------------------------------------------------- I
中文摘要 ------------------------------------------------------------------------ II
英文摘要 ----------------------------------------------------------------------- IV
第一章 緒論
1.1 過敏 -------------------------------------------------------------------- 1
1.2 過敏的分型 ----------------------------------------------------------- 2
1.3 與過敏有關的疾病 -------------------------------------------------- 5
1.4 過敏疾病的現況 ------------------------------------------------------5
1.5 過敏疾病的治療 ----------------------------------------------------- 6
1.6 過敏原 ------------------------------------------------------------------8
1.6.1 家塵蟎 ---------------------------------------------------------- 9
1.6.2 黴菌 --------------------------------------------------------------9
1.6.3 蟑螂 ------------------------------------------------------------- 9
1.6.4花粉 -------------------------------------------------------------- 9
1.6.5 寵物過敏原 -------------------------------------------------- 10
1.6.6食物過敏原 --------------------------------------------------- 10
1.7 常見過敏原的盛行率 ---------------------------------------------- 11
1.8 益生菌 ---------------------------------------------------------------- 12
1.8.1 益生菌適應症之研究 -------------------------------------- 14
1.8.2 鼠李糖乳桿菌Lactobacillus rhamnosus GG ----------- 16
第二章 研究動機 ---------------------------------------------------- 17
第三章 材料與方法
3.1 益生菌LGG之備製 ------------------------------------------------ 18
3.2 皮脂類固醇 ---------------------------------------------------------- 18
3.3 過敏原之備製 ------------------------------------------------------- 18
3.3.1 OVA雞卵蛋白 ------------------------------------------------ 18
3.3.2 GST-Der pII1-129塵蟎蛋白製備---------------------------------------- 18
3.4 動物實驗 ------------------------------------------------------------- 21
3.4.1 動物實驗致敏原之使用 ------------------------------------ 21
3.4.2 動物致敏模式 ------------------------------------------------ 22
3.4.3 致敏原急性期（28天）致敏模式 ------------------------- 22
3.4.4 致敏原慢性期（76天）致敏模式 ------------------------- 23
3.4.5 實驗動物分組 ------------------------------------------------ 24
3.5 血清中OVA-specific-IgE、IgG1、IgG2a測定 ---------------- 24
3.6 肺泡沖洗液中血球的分類計數 ---------------------------------- 25
3.7 血清與細胞沖洗液中各種細胞激素的測定 ------------------- 26
3.8 MMPs之檢測 -------------------------------------------------------- 27
3.9 肺部組織病理切片 ------------------------------------------------- 28
3.10 統計分析 ------------------------------------------------------------ 28
第四章 研究結果
4.1 益生菌LGG對於急性期OVA致敏鼠在AHR的影響 -----29
4.2 益生菌LGG對於急性期OVA致敏鼠在血清中OVA-specific IgE與OVA- pecific-IgG2a的表現 ------------------------------------29
4.3 益生菌LGG對於急性期OVA致敏鼠在呼吸道發炎細胞浸潤上的影響 ---------------------------------------------------------------30
4.4 益生菌LGG對於急性期OVA致敏鼠在血清與肺泡沖洗液中各種細胞激素之影響 ------------------------------------------------30
4.5 益生菌LGG對於急性期OVA致敏鼠在肺部MMP9表現量的影響 ---------------------------------------------------------------------31
4.6 益生菌LGG對於慢性期致敏模式在AHR上的影響 --------33
4.7 益生菌LGG對於慢性期致敏模式在血清中OVA-specific-IgE與OVA-specific-IgG2a的表現 ------------------------------------33
4.8 益生菌LGG對於慢性期致敏模式在呼吸道細胞浸潤的影響 -----------------------------------------------------------------------------34
4.9 益生菌LGG對於慢性期致敏模式在BALF中各種細胞激素的影響------------------------------------------------------------------34
4.10 益生菌LGG對於慢性期致敏模式在肺部組織中IL-17 與 TNF-α表現量之影響 ------------------------------------------------35
4.11 益生菌LGG對於慢性期致敏模式在呼吸道膠原蛋白沈澱(collagen deposition) 之影響 --------------------------------------35
4.12 急性期OVA致敏模式與Der pII1-129 塵蟎蛋白致敏動物模式在呼吸道過度反應的表現-------------------------------------37
4.13 急性期OVA致敏模式與Der pII1-129 塵蟎蛋白致敏動物模式在血清中specific-IgE與specific-IgG1之表現 -----------37
4.14 急性期OVA致敏模式與Der pII1-129 塵蟎蛋白致敏動物模式在各種細胞激素之表現 ---------------------------------------38
4.15 性期OVA致敏模式與Der pII1-129 塵蟎蛋白致敏動物模式在肺部發炎細胞浸潤之表現 ------------------------------------38
4.16 急性期OVA致敏模式與Der pII1-129 塵蟎蛋白致敏動物模式在呼吸道發炎現象之表現-------------------------------------39
4.17 益生菌LGG對於急性期Der pII1-129塵蟎蛋白致敏鼠在AHR上的影響 --------------------------------------------------------40
4.18 益生菌LGG對於急性期Der pII1-129塵蟎蛋白致敏鼠在血清中Der pII1-129-specific-IgE與Der pII1-129-specific-IgG2a的表現 ----------------------------------------------------------41
4.19 益生菌LGG對於急性期Der pII1-129塵蟎蛋白致敏鼠在呼吸道發炎細胞浸潤上的影響 ------------------------------------41
4.20 益生菌LGG對於急性期Der pII1-129塵蟎蛋白致敏鼠在肺泡沖洗液中細胞激素的影響 ------------------------------------42
4.21 益生菌LGG對於急性期Der pII1-129塵蟎蛋白致敏鼠在呼吸道發炎上的影響-------------------------------------------------42
4.22 益生菌LGG合併皮脂類固醇Prednisolone使用對於急性期Der pII1-129塵蟎蛋白致敏鼠AHR之影響---------------------44
4.23 益生菌LGG合併皮脂類固醇Prednisolone使用對於急性期Der pII1-129塵蟎蛋白致敏鼠血清中Der pII1-129-specific-IgE/IgG1/ IgG2a之影響 --------------------------------------------45
4.24 益生菌LGG合併皮脂類固醇Prednisolone使用對於急性期Der pII1-129塵蟎蛋白致敏鼠對於各種細胞激素表現量之影響 ------------------------------------------------------------------------45
4.25 益生菌LGG合併皮脂類固醇Prednisolone使用對於急性期Der pII1-129塵蟎蛋白致敏鼠肺部發炎細胞浸潤之影響-----46
4.26 益生菌LGG合併皮脂類固醇Prednisolone使用對於急性期Der pII1-129塵蟎蛋白致敏鼠呼吸道發炎狀況之影響 ------46

第五章 討論 ------------------------------------------------------------------- 48
第六章 結論與建議 ---------------------------------------------------------- 54
參考文獻 ----------------------------------------------------------------------- 55
圖表說明 ----------------------------------------------------------------------- 71
附錄 (投稿論文抽印本與排名)

圖目錄
Figure 1. The protocols for the mouse models of acute allergic asthma. -------------------------------------------------------------------------- 71
Figure 2. The protocols for the mouse models of chronic allergic asthma. -------------------------------------------------------------------------- 72
Figure 3. The effect of LGG treatment in AHR in OVA-sensitization animal model ------------------------------------------------------------------- 73
Figure 4. The effect of LGG treatment in infiltrating cells of the lungs in OVA-sensitization animal model ---------------------------------------- 74
Figure 5. The effect of LGG on AHR in chronic stage OVA-sensitization model ---------------------------------------------------------- 75
Figure 6. LGG treatment in infiltrating cells of the lungs in chronic stage with OVA-sensitization animal model -------------------------------76
Figure 7. LGG affects IL-17 and TNF-α expression in chronic stage with OVA-sensitization animal model--------------------------------------77
Figure 8. LGG affects collagen deposition in lung tissue in chronic stage with OVA-sensitization animal model ----------------------------- 78
Figure 9. The different on AHR in OVA or Der pII1-129-sensitization mice------------------------------------------------------------------------------- 79
Figure 10. The different on OVA-specific IgE/IgG1 and Der pII1-129-specific IgE/IgG1 in serum in OVA or Der pII1-129-sensitization mice -------------------------------------------------------------------------------------- 80
Figure 11. The different on differential cytokines expression in BALF in OVA or Der pII1-129- sensitization mice -------------------------------- 81
Figure 12. The difference of infiltrating cells of the lungs in OVA or Der pII1-129- sensitization mice ---------------------------------------------- 82
Figure 13. The different of lung inflammation in BALF in OVA or Der pII1-129- sensitization mice ---------------------------------------------------- 83
Figure 14. The effect of LGG treatment in AHR in Der pII1-129-sensitization animal model --------------------------------------------------- 84
Figure 15. The effect of LGG of infiltrating cells of the lungs in Der pII1-129-sensitization mice----------------------------------------------------- 85
Figure 16. The effect of LGG of lung inflammation in Der pII1-129-sensitization mice ------------------------------------------------------------- 86
Figure 17. The effect of LGG and Prednisolone on AHR ------------ 87
Figure 18. The effect of LGG and Prednisolone on differential cytokines express in BALF in Der pII1-129-sensitization mice --------- 88
Figure 19. The effect of LGG and Prednisolone of infiltrating cells of the lungs in Der pII1-129-sensitization mice ---------------------------------89
Figure 20. The effect of LGG and Prednisolone of lung inflammation in BALF in Der pII1-129-sensitization mice ---------------------------------90
表目錄
Table 1. The effects of the LGG treatment on OVA-specific-IgE/IgG2a in serum. -----------------------------------------------------------91
Table 2. The effect of LGG on cytokines in BALF in OVA-sensitization animal model in BALF. Data points represent the median +/- IQR of the individual mouse groups. ----------------------- 92
Table 3. The effects of the LGG treatment on MMP9 expression in serum and BAL ---------------------------------------------------------------- 93
Table 4. The effects of the LGG treatment on OVA-specific-IgE/IgG2a in serum in chronic stage. ---------------------------------------------------- 94
Table 5. The effect of LGG in acute stage of Der pII1-129-specific antibodies in serum. Data points represent the median +/- IQR of the individual mouse groups ----------------------------------------------------- 95
Table 6. The effect of LGG on cytokines in BALF in Der pII1-129-sensitization animal model in BALF. Data points represent the median +/- IQR of the individual mouse groups. ---------------------------------- 96
Table 7. LGG and Prednisolone on Der pII1-129-specific IgE/IgG1/ IgG2a in serum in Der pII1-129-sensitization mice Data points represent the median +/- IQR of the individual mouse groups -------------------- 97

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