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研究生:李育慈
研究生(外文):Yu-tzu
論文名稱:口服金針菇免疫調節蛋白預防及治療致敏小鼠之研究
論文名稱(外文):The study of prevent and treatment asthma in mice model with FIP-fve
指導教授:呂克桓呂克桓引用關係李宣信李宣信引用關係
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:公共衛生學系碩士班
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:58
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近年來氣喘的發生率持續的快速增加,因此針對氣喘所做的研究也愈
來愈多而治療過敏氣喘的新藥也不斷的被開發出來,而目前對於氣喘的治療藥物多以症狀緩解為主,此外在未來則是以了解氣喘的完整機制以及發展有效抑制氣喘發炎反應之藥物為主要目標。目前針對金針菇免疫調節蛋白(fungal immunomodulatory protein-fve, FIP-fve)的研究指出,金針菇免疫調節蛋白是由新鮮金針菇萃取而來,而此蛋白具有抗腫瘤、抗病毒、抗菌以及降低膽固醇等活性,另外研究中亦顯示此蛋白具有刺激人類周邊血淋巴球細胞以及增強免疫細胞中的細胞激素如IL-2 與IFN-γ。因此在本研究中我們想了解金針菇免疫調節蛋白對於致敏小鼠模型中呼吸道發炎反應的影響。
本研究是使用BALB/c母鼠以雞卵蛋白 (chicken ovalbumin, OVA)誘發小鼠產生致敏的現象,實驗中在第1天至第3天及第14天進行OVA腹腔注射進行致敏作用並於第14、17、21、24及27天進行OVA鼻腔吸入動作,此動物實驗模式已建立完成。此外本研究將致敏小鼠隨機分為2組,一組將FIP-fve餵食於實驗進程第0天至第14天此組的意義為探究FIP-fve對於氣喘疾病預防的效果,另一組則為實驗進程第14天至第27天餵食致敏小鼠FIP-fve此組別則為探究FIP-fve對於氣喘的治療效果。而在本研究的對照組則是以生理實鹽水進行並做為非致敏小鼠之對照。根據研究結果顯示,OVA致敏小鼠具有的明顯呼吸道發炎反應現象會經由前後給予口服FIP-fve而受到抑制。呼吸道過度反應現象是藉由methacholine刺激致敏小鼠後所獲得。而無論是前或後給予口服FIP-fve都能回復呼吸道過度反應現象。另外在致敏小鼠的血清及肺泡沖洗液中(bronchoalveolar lavage fluid, BALF)其IgE、IL-4、IL-10都有明顯增加而IFN-γ與TGF-β則有明顯減少的現象,但這些現象在前後給予口服FIP-fve的致敏小鼠中都會獲得改善。
本研究可發現口服FIP-fve對於OVA引起的呼吸道發炎反應具有抗發
炎的效果,而口服FIP-fve對於過敏性呼吸道疾病可能是一項很好的替代性治療方式。

The incidence of asthma has increased substantially in the last two decades. New medication is developed rapidly in recent years to apply to allergic asthma, since lots of people have investigated about the issue.
However, now existing drugs just offer partial relief of symptoms in such disease. The goal of feature is to understand the complicated mechanism of asthma, and develop more effective drugs for suppressing the inflammatory
response in asthma. The golden needle mushroom, Flammulina velutipes, and extracts, possess immunomodulatory, anti-tumor, anti-viral, anti-fungal and cholesterol-lowering activities. A major fruiting body protein, designated Fve
or FIP-fve, was isolated and very likely plays a significant role in the mushroom’s immunomodulating effects. It stimulates mitogenesis of human
peripheral lymphocytes and enhances the transcription of interleukin-2 (IL-2), interferon-g (IFN-γ).
We examined the role of agent of edible golden needle mushroom extract FIP-fve in a mouse asthma model after allergen-induced chronic airway inflammation. Female BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on days 1 to 3 and 14, received intranasal OVA on days 14, 17, 21, 24 and Days 27. The mouse asthma model with airway inflammation by airway mucus release and infiltration by eosinophils was set up. The sensitized mice were divided into 2 groups. One group, the sensitized mice will be fed
with FIP-fve on days0 to days14 meaning prevention. Another group, the sensitized mice will be fed with FIP-fve on days14 to days28 meaning treatment. In this mouse asthma model, normal saline was used as a positive control. The non-sensitized mice were used as a negative control. The results show that OVA-sensitized mice developed a significant airway inflammatory response that was inhibited by pre- and post treated with FIP-fve. Airway hyperresponsiveness to methacholine was observed in OVA-sensitized mice. Both pre- and post-treated with FIP-fve reversed airway hyperresponsiveness. An increase in IgE, IL-4, IL-10 and a decrease in IFN-γ, TGF-βin bronchoalveolar lavage fluid (BALF) and sera were found in OVA-sensitized
mice, but were reversed by both pre- and post- treated with FIP-fve.
From this study, oral FIP-fve could produce an anti-inflammatory effect on OVA-induced airway inflammation and oral FIP-fve might be a good alternative therapy for allergic airway disease.

目 錄 頁次
致 謝..................................................... I
中文摘要 .................................................II
英文摘要 ................................................III
第一章 前言
1.1 氣喘(Asthma) ..........................................1
1.2 氣喘的致病機喘........................................ 4
1.2.1 氣喘之病理切片應具有之特徵 ..........................4
1.2.2 氣喘主要之臨床表現包括有 ............................5
1.2.3 氣喘之免疫機制 ......................................5
1.3 丙型干擾素 (IFN-γ)
1.3.1 IFN-γ的產生及其功能 ................................7
1.3.2 IFN-γ所誘發之訊號傳遞反應 ..........................8
1.3.3 IFN-γ於免疫系統中所扮演之角 ........................9
1.3.4 IFN-γ與氣喘之關聯 .................................10
1.3.5 IFN-γ基因之多型性研究 .............................11
1.4 氣喘的治療............................................12
1.5 金針菇萃取物(FIP-fve)
1.5.1 金針菇免疫調節蛋白 .................................13
1.5.2 金針菇免疫調節蛋白之生理活性 .......................14
1.6 研究動機與目的 .......................................15
第二章 材料與方法
2.1 實驗動物 .............................................15
2.2 FIP-fve 的分離與純化
2.2.1 FIP-fve 的分離與純化 ...............................16
2.2.2 FIP-fve 純化結果 ...................................17
2.3 SDS-聚丙烯醯銨板膠電泳法
2.3.1 SDS-聚丙烯醯銨板膠電泳法之製備 .....................17
2.3.2 SDS-PAGE 之電泳操作 ................................18
2.3.3 染色與褪色 .........................................18
2.3.4 染色液與退色液的製備 ...............................18
2.4進行ovalbumin 致敏模式與施予FIP-fve
2.4.1 致敏流程 ...........................................19
2.4.2 施藥時間與劑量 .....................................20
2.4.3 呼吸道阻力測定 (AHR) ...............................20
2.4.4 小鼠血液樣本採集................................... 21
2.4.5 肺泡沖洗(BALF)及細胞處理........................... 21
2.4.6 肺臟組織病理切片處理 ...............................22
2.5 血清中OVA-specific IgE、IgG1、IgG2a之濃度測定
2.5.1 OVA-specific IgE ...................................22
2.5.2 OVA-specific IgG2a .................................23
2.6 小鼠IL-4、IL-10、TGF-β及INF-γ之濃度測定
2.6.1 血清及肺泡沖洗液中之INF-γ 濃度測定 ................23
2.6.2 血清及肺泡沖洗液中之IL-4、IL-10 濃度測定. ..........24
2.6.3 血清及肺泡沖洗液中之TGF-β 濃度測定 ................25
2.7 統計分析............................................. 25
第三章 結果
3.1 FIP-fve 對氣喘小鼠之作用
3.1.1 FIP-fve 能有效降低呼吸道過度反應 ...................26
3.1.2 小鼠血清中OVA-specific antibodies 的表現............27
3.1.3 FIP-fve 能有效減少嗜伊紅性白血球於小鼠
呼吸道浸潤的現象 ...................................27
3.1.4 FIP-fve 能降低小鼠血清及肺部沖洗液裡
IL-4 之表現 ........................................29
3.1.5 FIP-fve 能增加小鼠血清及肺部沖洗液裡
IFN-γ之表現 .......................................30
3.1.6 給予口服FIP-fve 之小鼠血清及肺部沖洗液中
IL-10 ..............................................31
3.1.7 給予口服FIP-fve 之小鼠血清及肺部沖洗液中
TGF-β之表現 .......................................32
3.1.8 FIP-fve 能有效減少小鼠呼吸道之發炎現象 32
第四章 討論 ..............................................34
圖目錄
圖1. 金針菇免疫調節蛋白萃取簡圖 ..........................40
圖2. 金針菇免疫調節蛋白純化結果 ..........................41
圖3. 以OVA 進行小鼠進行致敏之流程 ........................41
圖4. pre FIP-fve 組實驗過程...............................42
圖5. post FIP-fve 組實驗過程 .............................42
圖6. FIP-fve 對小鼠呼吸道阻力(AHR)之影響 .................43
圖7. FIP-fve 對致敏小鼠血清中裡OVA-specific IgE
與IgG2a 之影響 ......................................44
圖8. FIP-fve 對致敏小鼠肺泡沖洗液中嗜伊紅性白血球(E)、
淋巴球(L)、單核球(M)百分比之影響 ....................45
圖9. FIP-fve 對致敏小鼠肺泡沖洗液中嗜伊紅性白血球(E)、
淋巴球(L)、單核球(M)數量之影響 ......................46
圖10. FIP-fve 對致敏小鼠血清及肺泡沖洗液裡IL-4 之影響 ....47
圖11. FIP-fve 對致敏小鼠血清及肺泡沖洗液裡IFN-γ之影響 ...48
圖12. FIP-fve 對致敏小鼠血清及肺泡沖洗液裡IL-10 之影響 ...49
圖13. FIP-fve 對致敏小鼠血清及肺泡沖洗液裡TGF-β之影響 ...50
圖14. FIP-fve 對致敏小鼠氣管發炎狀況之影響以病理切片呈現..51
參考文獻 .................................................52

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