臺灣博碩士論文加值系統

過敏性氣喘為一種慢性呼吸道過度反應，常伴隨著肺部發炎、嗜酸性白血球浸潤與血清中IgE含量增加。已有研究指出鹿茸在體外試驗中可抑制大鼠腹股溝淋巴結生成IL-2，亦可抑制發炎物質前驅物的細胞激素例如IL-1β、IL-6、TNF-α。而臨床試驗發現，氣喘孩童在不停用西藥下，同時服用鹿茸後，血清中組織胺、白三烯素C4有下降的趨勢，且IFN-γ增加，但其相關機制不明。因此本研究希望能藉由動物模式來進一步探討鹿茸對於呼吸道過度反應之調節作用。試驗中以卵白蛋白致敏八週齡BALB/c雌鼠誘發其呼吸道過度反應，以口服方式餵食小鼠不同劑量之鹿茸酒精萃取物（50、100、300 mg/kg），並以皮質類固醇（10 mg/kg）作為正對照組。七週後測量其呼吸道阻力，並犧牲小鼠收集頸部氣管週邊淋巴結、肺部沖洗液、脾、胸腺、肺等，進行淋巴細胞表面標記分析（CD3, CD4, CD8, CD19, CD25, CD69, CD278, Tim-3）、抗卵白蛋白抗體（Anti-OVA-IgE, Anti-OVA-IgG1, Anti-OVA-IgG2a）及細胞激素（IL-4, IL-5, IFN-γ）測定、肺部沖洗液中血球形態區分、蘇木素與嗜伊紅染色法（Hematoxylin-eosin stain）和過碘酸希夫染色（Periodic acid-Schiff stain）評估肺部組織病理切片中細胞浸潤、氣管受損及黏液分泌情形。結果顯示經過卵白蛋白致敏後，鹿茸萃取物可增加肺部沖洗液中Th1細胞（Tim-3, CD4+）比例，減少脾臟淋巴細胞中Th2（CD278+, CD4+）細胞比例；且降低肺部沖洗液中IL-4與IL-5分泌量、降低血清及肺部沖洗液中抗卵白蛋白IgE與IgG1生成，提高其抗卵白蛋白IgG2a生成量；並減少肺部支氣管週邊細胞浸潤情形及嗜酸性白血球數量；減少肺泡壁發炎反應、靜脈週邊區域中、動脈週邊與支氣管週邊區域中發炎細胞浸潤；進而顯著性減緩呼吸道過度反應。進一步利用細胞試驗來解明分子調控之機轉。以鹿茸萃取物或鹿茸不同極性萃取層刺激EL4細胞株及RAW 264.7細胞株觀察其細胞激素的分泌調控。鹿茸萃取物（10.0 μg/ml）可顯著性提高EL4細胞的IFN-γ分泌量，而鹿茸氯仿萃取物可提升Raw 264.7細胞的IL-12分泌量。綜上所述，鹿茸可透過活化全身性之T調節細胞、調節naïve T細胞分化趨向Th1 cells、進而降低過敏性IgE抗體生成與發炎細胞於肺部浸潤來降低呼吸道過度反應。

Allergic asthma is a chronic disease associated with airway hyperresponsiveness such as bronchial inflammation, eosinophils infiltration and increase of serum IgE. Previous in vitro studies were reported that velvet antler can decrease the production of IL-2, and suppress pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α. Otherwise, in the clinical study, it was discovered that the concentration of histamine and leucotriene were decreased and IFN- was increased in serum of asthmatic children after velvet antler treatment. But the relative mechanism is still unclear. In this study, we established the animal model to realize the effect of velvet antler (VA) in airway hyperresponsiveness. Female BALB/c mice were sensitized and challenged with ovalbumin (OVA) to induce airway hyperresponsiveness and administered with various doses of velvet antler (50, 100, and 300 mg/kg) or prednisolone (10 mg/kg) for seven weeks. After seven weeks treatments, mice were determined the enhanced pause (Penh) using whole body plethysmograpy, pulmonary cell infiltration and T cell differentiation, anti-OVA antibodies (including Anti-OVA-IgE, Anti-OVA-IgG1, Anti-OVA-IgG2a) and cytokines (such as IL-4, IL-5, IFN-γ) analysis, the paraffin section of lung for hematoxylin-eosin stain and periodic acid-Schiff stain. The results indicated that Velvet antler extracts (VAE) could increase the Th1 cells (Tim-3, CD4+) and reduce the Th2 cells (CD278+, CD4+) and to modulate T helper cell differentiation. VAE significantly decreased the secretion of IL-4 and IL-5 in bronchoalveolar lavage fluid (BALF) of asthmatic mice. Anti-OVA IgE and IgG1 were significantly decreased and anti-OVA IgG2a were significantly increased in serum and BALF of asthmatic mice. It also decreased the leukocytes infiltration and eosinophils counts in BALF. Moreover, VAE reduced the infiltration in perivenous regions and periarterial and periboronchial regions and inflammation in alveolar wall. VAE significantly decrease Penh after OVA challenged in allergic BALB/c mice. Furthermore, we used in vitro cell culture system to determinate the molecular regulation mechanism. Various doses of VAE or VAE fractions were treated EL4 cells and RAW 264.7 cells to observe their cytokines modulation. It was showed that VAE significantly raised the production of IFN-γ in EL4 cells. The chloroform fraction of VA stimulated the IL-12 expression in RAW 264.7 cells. It suggested that velvet antler might effectively modulate Treg cells, regulate T cells tend to th1 cells differentiation, down-regulated allergic IgE and inflammatory cells infiltration to regulated airway hyperresponsiveness.

壹、 摘要 1
貳、 前言 5
參、 文獻探討 7
一、 鹿茸 7
(一) 鹿茸來源與型態 7
(二) 鹿茸分類 8
(三) 鹿茸品質鑑別 8
(四) 鹿茸之組成份 9
(五) 鹿茸之藥理作用 10
(六) 鹿茸之毒性與副作用 11
二、 氣喘 12
(一) 氣喘定義 12
(二) 氣喘盛行率及死亡率 12
(三) 氣喘病理特徵 13
(四) 免疫系統 13
(五) 氣喘相關分子 14
(六) 氣喘相關細胞表面抗原分子介紹 16
(七) 氣喘致病機轉 17
(八) 氣喘治療 19
肆、 研究目的 21
伍、 材料方法 22
一、 實驗材料 22
二、 實驗方法 24
(一) 動物飼養與分組 24
(二) 鹿茸萃取物製備流程 24
(三) 動物致敏模式 25
(四) 樣品收集 25
(五) 樣品分析 26
(六) 以EL4細胞株和Raw264.7細胞株模擬體內細胞 29
陸、 統計分析 31
柒、 結果 32
一、 小鼠呼吸道過度反應之免疫調節 32
(一) 小鼠體重、脾臟、胸線與肺臟重量之變化 32
(二) 呼吸道過度反應中肺部沖洗液細胞總數之變化 32
(三) 呼吸道過度反應中呼吸道週邊淋巴細胞次族群之變化 32
(四) 呼吸道過度反應中肺部沖洗液淋巴細胞次族群之變化 33
(五) 呼吸道過度反應中脾臟淋巴細胞次族群之變化 34
(六) 呼吸道過度反應中肺部沖洗液細胞激素之變化 35
(七) 呼吸道過度反應中血清與肺部沖洗液特異性抗體之變化 35
(八) 呼吸道過度反應中肺部沖洗液細胞浸潤種類之變化 36
(九) 肺部組織病理切片之變化 36
(十) 小鼠呼吸道過度反應之變化 37
二、 以細胞模式模擬體內細胞反應 37
(一) EL4細胞株生長週期 37
(二) EL4細胞經鹿茸萃取物刺激後細胞增生之效果 37
(三) EL4細胞經鹿茸萃取物刺激後分泌細胞激素之變化 38
(四) EL4細胞經鹿茸不同極性萃取層刺激後細胞激素之變化 38
(五) Raw 264.7細胞經鹿茸不同極性萃取層刺激後細胞激素之變化 38
捌、 討論 39
一、 呼吸道過度反應中T細胞之分化 39
二、 呼吸道過度反應中IgE之生成 40
三、 呼吸道過度反應中經過免疫調節支氣管病理狀況 41
四、 以細胞模式模擬體內細胞 42
玖、 結論 43
壹拾、 參考文獻 44
壹拾壹、 附錄 51
壹拾貳、 附表 84
壹拾參、 附圖 88
壹拾肆、 附件 94

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