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研究生: 黃鈺涵
論文名稱: 中鏈脂肪酸對痤瘡桿菌誘導發炎反應之影響
Effects of medium chain fatty acid on arachidonic acid and Propionibacterium acnes-induced inflammation
指導教授: 蔡帛蓉
Tsai, Po-Jung
學位類別: 碩士
Master
系所名稱: 人類發展與家庭學系
Department of Human Development and Family Studies
論文出版年: 2014
畢業學年度: 102
語文別: 中文
論文頁數: 89
中文關鍵詞: 痤瘡痤瘡桿菌中鏈脂肪酸發炎
英文關鍵詞: acne, P. acnes, medium chain fatty acid, inflammation
論文種類: 學術論文
相關次數: 點閱:149下載:15
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  • 尋常性痤瘡(acne vulgaris)又稱青春痘,除了好發於青春期男女外,在成年人也常見。其致病因子複雜,包括過多皮脂分泌(sebaceous hyperproductiom)、毛囊過度角化(follicular hyperkeratinization)、氧化壓力、發炎反應(periglandular dermal inflammation)和男性賀爾蒙都可能造成尋常性痤瘡的發生。痤瘡發展過程中痤瘡桿菌(P. acnes)被認為扮演重要的角色,P. acnes在阻塞的皮脂腺內大量繁殖會吸引單核球細胞(monocytes),而藉由活化單核球細胞與角質細胞的toll-like receptor,啟動其下游的訊息傳遞路徑使發炎介質產生而誘導痤瘡發炎;另外P. acnes誘發產生活性氧分子(ROS)也參與發炎反應。中鏈脂肪酸包括caproic acid (C6:0), caprylic acid (C8:0), capric acid (C10:0)和lauric acid (C12:0)。
    本研究目的為:以THP-1細胞以及皮脂腺細胞SZ95,探討中鏈脂肪酸對於痤瘡桿菌誘導發炎反應的影響。capric acid於本實驗室先前的研究結果顯示可降低in vitro實驗中以P. acnes誘導THP-1 monocytes產生的促發炎激素IL-8, TNF-aIL-1B,而將P. acnes與capric acid注射進ICR小鼠耳朵的in vivo實驗結果顯示可以減少小鼠耳朵因P. acnes.造成的腫脹與重量。
    以broth dilution method實驗的結果發現capric acid在高濃度時能抑制痤瘡桿菌生長;三種中鏈脂肪酸皆能夠減少P. acnes刺激THP-1 monocytes所產生的促發炎細胞激素TNF-a, IL-8,IL-1蛋白質和mR。
    capric acid IC50為22.9 M,以capric acid作為後續機制探討的樣品,結果顯示capric acid在25, 50, 100 M,皆可以顯著降低p38, ERK, JNK, p65蛋白質磷酸化的表現;於in vivo抗發炎實驗中顯示,三種中鏈脂肪酸能夠抑制P. acnes誘發的發炎反應與耳朵腫脹現象。
    另外,花生四烯酸(AA)會使P. acnes誘使THP-1產生的IL-8增加,且也同時增加皮脂腺脂質的堆積。capric acid則會降低單獨P.acnes和AA+P.acnes產生的IL-8;另外SZ95預處理AA後,AA+P.acnes組產生的IL-8高於單獨 AA 組別;capric acid會降低單獨P.acnes和AA+P.acnes產生的IL-8。

    Acne vulgaris is a common skin disease involving pilosebaceous follicle. The pathogenesis of acne vulgaris is multifactorial, including increased sebum production, comedogenesis and Propionibacterium acnes proliferation. P. acnes plays an important role not only in the process of inflammation but also in the formation of comedones. Previous studies have shown that P. acnes is one of the most important factors in acne. P. acnes activate toll-like receptor-2 on monocytes, which triggers the release of proinflammatory mediators(TNF-, IL-8), some studies have found that reactive oxygen species (ROS) will participate in the progression of acne. Medium chain fatty acid(MCFA)including caproic acid (C6:0), caprylic acid (C8:0), capric acid (C10:0)和lauric acid (C12:0).
    We investigated the effect of MCFA on inflammation caused by P. acnes.Human monocytes THP-1 cells and SZ95 were treated with P. acnes alone or in the presence of MCFA.Our previous studies have shown capric acid, lauric acid reduced P. acnes would activate monocytes to secrete pro-inflammatory cytokines.In addition, capric acid, lauric acid reduced P. acnes-induced inflammation of mice ear and then showed in vivo anti-inflammatory activity.
    Our results showed capric acid effectively inhibited the growth of P. acnes. Capric acid, caprylic acid and caproic acid potently suppressed the production of pro-inflammatory cytokines such as tumor necrosis factor-, interleukin (IL)-8, and IL-1B by human monocytes THP-1 cells stimulated with P. acnes.
    The IC50 of capric acid was 22.9 M, we further evaluated the anti-inflammatory mechanism of capric acid, the results showed that significantly inhibited P. acnes-enhanced phosphorylation of p38, ERK, JNK and p65.MCFA reduced P. acnes-induced inflammation of mice ear and showed in vivo anti-inflammatory activity.
      Arachidonic acid(AA) significantly enhanced IL-8 by P. acnes-stimulated THP-1 cells, and AA stimulated lipogenesis of SZ95 sebocyte. Capric acid reduced P. acnes-induced and AA+ P. acnes-induced IL-8 expression.In addition, pretreatment with AA stimulated enhanced IL-8 by P. acnes- stimulated SZ95 sebocyte, Capric acid reduced P. acnes-induced and AA+ P. acnes-induced IL-8 expression.

    第一章 緒論 1 一、研究動機 1 二、研究目的 2 第二章 文獻探討 3 第一節 皮膚結構 3 第二節 痤瘡的致病機制 6 壹、痤瘡的成因 6 貳、痤瘡桿菌與發炎反應 10 一、 Toll-like receptors (TLRs) 11 二、 痤瘡桿菌誘導之促發炎細胞激素 13 三、 Arachidonic acid signaling pathway 13 第三節 痤瘡的治療 16 第四節 實驗材料 17 一、 脂肪酸 17 第三章 材料與方法 19 第一節 研究材料 19 一、 實驗架構 19 二、 藥品與試劑 20 三、 儀器設備與耗材 24 四、 細胞培養 25 五、 細菌培養 27 第二節 實驗方法 28 一、 抑菌實驗 28 二、 細胞存活率測定 (MTT) 28 三、 抗發炎活性評估 29 四、 促發炎細胞激素mRNA表現量 30 五、 中鏈脂肪酸對於P. acnes-induced p-38, ERK, JNK磷酸化之影響 33 六、 轉錄因子nuclear factor-kappa B (NF-κB)活化分析 35 七、 動物實驗 (in vivo抗發炎能力評估) 36 八、 統計分析 40 第四章 結果 41 第一節中鏈脂肪酸之抑菌與抗發炎作用 41 壹、 抑菌實驗 41 貳、 細胞存活率測定(MTT) 43 第二節 評估中鏈脂肪酸的抗發炎能力 44 壹、In vitro抗發炎活性評估 44 貳、In vivo anti-inflammatory effect 53 參、中鏈脂肪酸對於P. acnes-induced MAPK pathway and NF-B磷酸化之影響 55 第三節capric acid對pretreated AA刺激P. acnes- induced IL-8之影響 61 第四節 脂質堆積 66 壹、細胞存活率測定(MTT) 66 貳、中鏈脂肪酸之SZ95脂質堆積的影響 67 參、AA之脂質堆積的影響 68 第五章 討論 69 一、抗發炎活性與作用機制 69 二、 In vivo抗發炎活性評估 79 三、 總結 81 第六章 參考文獻 82 第七章 附錄(動物實驗同意書) 89

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