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研究生:許家修
研究生(外文):Chia-Hsiu
論文名稱:選擇性半胱胺醯基白三烯素受體拮抗劑在老鼠氣喘模組上對基質金屬蛋白酵素表現調節之研究
論文名稱(外文):Selective Cysteinyl Leukotriene Receptor Antagonist Modulates Matrix Metalloproteinase Expression in a Mouse Asthma Model
指導教授:呂克桓呂克桓引用關係
指導教授(外文):Ko-Huang Lue
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:70
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過敏疾病包括過敏性鼻炎及氣喘,在台灣及全世界都是很常見的疾病。一般認為此病主要是環境及遺傳因素交互作用而造成的。在過去二十年間,氣喘疾病的發生率持續快速增加中。隨著越來越多人投入氣喘的研究,應用於治療過敏氣喘疾病的新藥劑因此不斷被開發出來。話雖如此,但目前已知的藥物僅能提供疾病症狀的部分舒解。因此我們的研究目的乃藉由不同藥物作用來探討其複雜的機制,以開發更多具功效的藥物來遏止氣喘的發炎反應產生,甚至更進一步可以回復已損傷重塑過的肺組織。
就現今已知的觀念,氣喘是一種複雜反覆慢性發炎的疾病,病理上的變化包括有肺部嗜酸性球的浸潤,水腫,黏液的過度分泌以及呼吸道的過度反應。而在長期氣喘的狀態下,呼吸道會產生杯狀細胞、上皮下纖維、平滑肌肉組織、血管等增生的呼吸道重塑現象,因而增加控制氣喘的困難度。目前的研究發現,有許多機轉、介質以及細胞素參與氣喘的過程形成,特別是半胱胺醯基白三烯素(CysLTs)對於整個氣喘的病理變化佔有重要的角色。我們的研究將利用老鼠氣喘模組,來探討選擇性半胱胺醯基白三烯素受體拮抗劑在氣道發炎及重塑的功效。
我們將BALB/C的母鼠,經過第0天與第14天的腹腔注射蛋清蛋白以及第14天與第25-27天給予經鼻的蛋清蛋白後,氣喘模組將會建立成功。隨後在氣喘模組建立過程的第15天至第27天,我們隨機選擇部分致敏的老鼠,分別予以餵食針餵食半胱胺醯基白三烯素受體拮抗劑singulair(montelukast, MK-476)、verlukast(MK-679)或安慰劑。另外目前已知具有抗發炎效果,且廣泛應用於臨床的類固醇類藥物去氫可體醇(prednisolone),也將會選擇一組致敏過的老鼠於上述時程予以餵食,當作治療成效的參考指標。在氣喘模組建立時程的第28天,老鼠在以非侵入性整體肺功能機測定肺功能後,將予以犧牲以取得血清、支氣管肺泡灌流液及肺組織,以進行氣道發炎及重塑反應的分析。
在我們的研究中,經由蛋清蛋白致敏過的老鼠,相較於對照組,會產生明顯的氣道發炎反應。不論在血清IgE值、支氣管肺泡灌流液中的嗜酸性球數、或呼吸道膠原沈積及支氣管周圍纖維化部份,蛋清蛋白致敏組皆有明顯的上昇(相較於對照組P < 0.001)。由蛋清蛋白致敏所造成的呼吸道發炎反應則可藉由prednisolone及montelukast的使用,來達到有效的抑制效果(相較於致敏組P < 0.01)。而在呼吸道重塑的過程當中,相較於prednisolone及montelukast,使用MK-679對呼吸道發炎反應的減緩,效果較不顯著(相較於致敏組P < 0.05);但對於回復呼吸道纖維化變化的部分,則效果與使用montelukast一樣(相較於致敏組P < 0.001),比使用prednisolone為佳。同時我們研究的結果也顯示,支氣管肺泡灌流液中基質金屬蛋白酵素(MMP)-2及9的含量,與呼吸道重塑的程度成正比。在蛋清蛋白致敏組上可以發現,由乙流丑甲基膽素(methacholine)所誘發的明顯氣道過度反應(相較於對照組P < 0.01)。不管使用prednisolone、montelukast或MK-679,皆可減緩此氣道過度反應的現象。不過當吸入高濃度的methacholine(20 mg/ml)時,只有使用prednisolone及montelukast,可以有意義的降低氣道過度反應至有效程度(相較於致敏組P < 0.05)。
總結來說,經由我們的研究可以知道,有許多細胞素(cytokine)參與呼吸道的發炎及重塑過程。而半胱胺醯基白三烯素在慢性呼吸道發炎的過程中,相較於其他細胞素,更佔有重要的地位。因此這可說明,為何選擇性半胱胺醯基白三烯素受體拮抗劑相較於prednisolone,對抑制呼吸道重塑具有更佳的效果。此外,我們的研究也顯示,基質金屬蛋白酵素-2及基質金屬蛋白酵素-9可作為監測呼吸道重塑的有利工具。


Atopic disease including allergic rhinitis and asthma is common in the world and Taiwan. The disease is generally considered to be caused by interaction of genetic and environmental factors. 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 these. However, now existing drugs just offer partial relief of symptoms in such disease. Therefore, the aim of our study was to investigate the complicated mechanism of asthma by different drugs. The more effective drugs to suppress asthmatic airway response are expectantly to be developed. Even we can then reverse the damaged lung tissue after airway remodeling.
As we known today, asthma is a repeated chronic inflammatory disease. It is characterized by a complex response of pulmonary eosinophilia, edema, mucus hypersecretion, and airway hyperreactivity. Under the condition of long-term asthma, airway remodeling may develop by goblet cells increased, subepithelial fibrosis, airway smooth muscle mass increased and vascular hyperplasia. These make asthma control more difficult. Many mechanisms, mediators and cytokines, including cysteinyl leukotrienes (CysLTs), are related to these structural changes. To determine the effect of a specific CysLT receptor antagonist on airway inflammation and remodeling, a mouse asthma model was applied.
BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on Days 0 and 14, were given intranasal OVA on Day 14 and Days 25-27. Randomized treatment groups of sensitized mice were fed a CysLT receptor antagonist singulair (montelukast, MK-476), verlukast (MK-679) or placebo from Days 15-27. Prednisolone is one kind of steroid which is known as efficient anti-inflammatory agent. It is used extensively at clinic for long time. One group of sensitized mice in the study would be fed with prednisolone according to the same feeding protocol as other study groups. The steroid-treated group will act as standard index of treatment efficacy. On Day 28, pulmonary mechanics were determined noninvasively using whole body plethysmography. The mice were then sacrificed; the serum, the bronchoalveolar lavage fluid (BALF) and the lung tissue were obtained for further evaluation of airway inflammation and remodeling.
In present study, the OVA-sensitized mice developed a significant airway inflammatory response than control group. The serum IgE level, the percentage of BALF eosinophils, the airway collagen deposition and peribronchial fibrosis were significantly elevated in OVA-sensitized group (P < 0.001 vs. control group). The significant airway inflammatory response in OVA-sensitized mice was inhibited by prednisolone or montelukast (P < 0.01 vs. sensitized group). MK-679, given during airway remodeling, reduced airway inflammation less effectively (P < 0.05 vs. sensitized group) but reversed structural changes more effectively (P < 0.001 vs. sensitized group) than prednisolone. Montelukast also reversed the airway structural changes to significant level as MK-679 (P < 0.001 vs. sensitized group). Here the study also showed that BALF matrix metalloproteinase (MMP)-2 and MMP-9 levels were proportional to the extent of airway remodeling. Airway hyperresponsiveness to methacholine was observed in OVA-sensitized mice (P < 0.01 vs. control group). Airway hyperresponsiveness could be reversed by prednisolone, montelukast and MK-679. However, when the OVA-sensitized mice were challenged with higher dose of methacholine (20mg/ml), only the prednisolone and montelukast reversed airway hyperresponsiveness to significant level (P < 0.05 vs. sensitized group).
In conclusion, this study demonstrates that many cytokines participate in airway inflammation and remodeling. The CysLT plays a more important role than other cytokines in chronic allergic airway inflammation. Thus the selective CysLT receptor antagonist inhibits airway remodeling more effectively than prednisolone. Furthermore, the MMP-2 and MMP-9 may be useful for monitoring airway remodeling.


中文摘要…………………………………………………………………1
英文摘要…………………………………………………………………4
目錄………………………………………………………………………8壹﹑前言……………………………………………………………….11
一﹑過敏疾病與形成之機制………………………………………….11
二﹑氣道過敏與重塑………………………………………………….16
三﹑氣道過敏的非侵入性評估與檢查……………………………….23
四﹑研究動機………………………………………………………….26
1.氣喘後呼吸道重塑的監測…………………………………………27
2.現有治療藥物的侷限………………………………………………27
3.尋求對氣道重塑具回復性的有效藥物……………………………28
貳﹑材料與方法……………………………………………………….30
一﹑材料……………………………………………………………….30
1. 研究動物來源…………………………………………………….30
二﹑方法……………………………………………………………….31
1.致敏及誘發氣道重塑………………………………………………31
2.白三烯素受體拮抗劑及去氫可體醇的介入治療…………………32
3.非侵入性整體肺功能測定…………………………………………33
4.定量特定血清抗體…………………………………………………34
5.支氣管肺泡灌洗液的獲取及細胞定量……………………………35
6.基質金屬蛋白酵素(MMP)-2及9的活性測量………………………36
7.肺組織病理分析……………………………………………………37
8.肝臟及腎臟組織分析………………………………………………38
9.統計…………………………………………………………………39
參﹑結果……………………………………………………………….40
一﹑血清IgE定量………………………………………………………40
二﹑支氣管肺泡灌洗液中嗜酸性球數分析………………………….41
三﹑氣道膠原沈積及支氣管周圍纖維化現象……………………….42
四﹑基質金屬蛋白酵素(MMP)-2及9的活性度……………………….44
五﹑非侵入性整體肺功能機測量結果……………………………….46
肆﹑討論……………………………………………………………….48
一﹑呼吸道發炎及重塑的表現……………………………………….48
二﹑藥物介入的影響………………………………………………….49
1.白三烯素受體拮抗劑與去氫可體醇在氣道發炎的角色比較……49
2.白三烯素受體拮抗劑與去氫可體醇在氣道重塑的角色比較……50
三﹑基質金屬蛋白酵素(MMP)與氣道重塑的相關性研究……………51
四﹑氣道過度反應現象的探討……………………………………….52
1.不同藥物介入的差異性反應研究…………………………………52
2.氣道過度反應與病理變化不一致性的原因探討…………………53
伍﹑結論與建議……………………………………………………….55
陸﹑參考文獻………………………………………………………….57
柒﹑圖表及其他附錄………………………………………………….65
一﹑圖一……………………………………………………………….65
二﹑圖二……………………………………………………………….66
三﹑圖三……………………………………………………………….67
四﹑圖四……………………………………………………………….68
五﹑圖五……………………………………………………………….69
六﹑圖六……………………………………………………………….70


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