異位性皮膚炎是一常見慢性發炎性皮膚疾病。雖然目前異位性皮膚炎發病機制尚不明確，但有許多研究認為異位性皮膚炎主要是由遺傳問題、環境因子、免疫失調以及皮膚屏障功能缺失所造成。除了發炎以外，血管新生以及氧化壓力同樣也參與異位性皮膚炎的病程並扮演著重要角色。至今，異位性皮膚炎治療用藥並無法完全治癒疾病且伴隨許多副作用產生。因此找尋一個能夠有效治療異位性皮膚炎的藥物是急迫需要的。許多海洋化合物被報導其生物活性具有抗腫瘤、抗發炎以及抗過敏等功效，而這些海洋化合物所擁有的生物活性可能成為發展新型異位性皮膚炎用藥的潛力物質。WH-4是一個合成軟珊瑚天然物之中間類似物購自商業公司。本研究中利用巨噬細胞RAW264.7作為離體模式檢測WH-4抗發炎以及抗氧化壓力的能力。在活體模式中使用轉殖型基因螢光蛋白斑馬魚檢測WH-4在血管新生中的效用。最後運用在異位性皮膚炎小鼠模式以檢測WH-4對於異位性皮膚炎的效用。實驗結果得知，本研究發現WH-4具有抗發炎、抗氧化壓力以及抗血管新生的功能。同樣的WH-4在異位性小鼠模式中可以降低因發炎、氧化壓力以及血管新生所造成的傷口。由以上實驗結果我們認為WH-4可能成為異位性皮膚炎的潛力用藥。

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. Although the detailed mechanisms of AD remain unclear, some studies indicated that genetic predisposition, environmental factors, immunological mechanisms and skin barrier dysfunction may cause AD mainly. On the other hand, AD is characterized by angiogenesis and oxidative stress which is major diagnostic criteria. Today, AD treatment could not totally cure AD but also have many side effect. Therefore, finding more effective drugs for AD is pressing need. Numbers of marine compounds were reported for their bioactivities such as anti-tumor, anti-inflammation and anti-allergy. WH-4 is a synthesized coral related compound obtained from commercial company. In our study, we used in vitro study to detect anti-inflammatory and anti-oxidation ability in RAW264.7, in vivo study we used Tg(fli1a:EGFP)y1 zebrafish to examine the antiangiogenic effect of WH-4. In addition, we also used mice model of AD to examine the effect of WH-4 on AD. In our result, we found that WH-4 had anti-inflammation, anti-oxidation and anti-angiogenesis activity. Also WH-4 could reduce the severity in AD mice model resulted from reducing inflammation, oxidative stress and angiogenesis. Based on above results, we demonstrate that WH-4 may be a potential drug for AD.

第一章、 前言 1
1.1 異位性皮膚炎流行病學之介紹 1
1.2 異位性皮膚炎之臨床特點及診斷方式 2
1.3 異位性皮膚炎致病因素 5
1.4 發炎在異位性皮膚炎所扮演之角色 5
1.5 巨噬細胞在異位性皮膚炎之關聯 9
1.6 氧化壓力與異位性皮膚炎之關聯 11
1.7 血管新生在異位性皮膚炎上之角色 13
1.8 現今臨床異位性皮膚炎用藥 17
1.8.1 局部皮質類固醇 (topical corticosteroids, TCSs) 18
1.8.2 局部鈣調磷酸酶抑制劑 (topical calcineurin inhibitors, TCIs) 19
1.9 異位性皮膚炎之實驗模式 21
1.10 海洋在藥物開發上之優勢 22
1.11 研究目的與動機 25
第二章、 材料與方法 27
2.1 離體細胞模式 27
2.1.1 細胞選用及藥物來源 27
2.1.2 細胞存活率測試 27
2.1.3 離體抗發炎模式 28
2.1.4 實驗分組 28
2.1.5 細胞蛋白質分析與西方墨點法 28
2.2 動物模式 29
2.2.1 動物照護 29
2.2.2 動物誘發模式 30
2.2.3 傷口給藥 30
2.2.4 傷口觀察 30
2.2.5 實驗分組&實驗流程圖 30
2.2.6 皮膚樣品蒐集與組織學分析 31
2.2.7 免疫組織化學染色 32
2.2.8 使用之目標抗體 34
2.2.9 組織前處理及蛋白質分析與西方墨點法 35
2.2.10 斑馬魚種及飼養條件 36
2.2.11 斑馬魚交配與胚胎培養 36
2.2.12 斑馬魚胚胎存活率測試 36
2.2.13 斑馬魚體節間血管新生 37
2.3 實驗數據分析 37
第三章、 實驗結果 38
3.1 細胞實驗結果 38
3.1.1 WH-4對老鼠巨噬細胞株RAW264.7存活率影響 38
3.1.2 WH-4對於LPS誘發老鼠巨噬細胞株RAW264.7發炎因子表現 38
3.1.2.1 WH-4對LPS誘發老鼠巨噬細胞株RAW264.7發炎性蛋白iNOS之影響 38
3.1.2.2 WH-4對LPS誘發老鼠巨噬細胞株RAW264.7發炎性蛋白COX-2之影響 39
3.1.3 WH-4對於LPS誘發老鼠巨噬細胞株RAW264.7抗氧化壓力蛋白HO-1表現量之影響 39
3.2 動物實驗結果 39
3.2.1 WH-4對斑馬魚 (AB strain Danio rerior) 胚胎存活率之影響 39
3.2.2 WH-4對Tg(fli1:EGFP)螢光斑馬魚仔魚之體節間血管(intersegmental vessel, ISV) 生成之影響 40
3.2.3 WH-4對於異位性皮膚炎 (atopic dermatitis, AD) 傷口外觀之影響 40
3.2.4 WH-4對於AD皮膚組織病理組織切片之影響 41
3.2.4.1 WH-4對於AD表皮不當增生之影響 41
3.2.4.2 WH-4對於AD免疫細胞浸潤程度之影響 41
3.2.5 WH-4對於AD皮膚組織中輔助性T細胞 (Th cell) 浸潤之影響 42
3.2.6 WH-4對於AD皮膚組織中IFN-表現之影響 42
3.2.7 WH-4對於AD皮膚組織中發炎蛋白質表現之影響 43
3.2.7.1 WH-4對於AD皮膚組織中發炎性蛋白iNOS表現量之影響 43
3.2.7.2 WH-4對於AD皮膚組織中發炎性蛋白COX-2表現量之影響 43
3.2.8 WH-4對於AD皮膚組織中抗氧化壓力蛋白HO-1表現之影響 43
3.2.9 WH-4對於AD皮膚組織中血管新生相關蛋白表現之影響 44
3.2.9.1 WH-4對於AD皮膚組織中血管新生相關蛋白VEGF-A表現量之影響 44
3.2.9.2 WH-4對於AD皮膚組織中血管新生相關蛋白CD31表現量之影響 44
3.2.9.3 WH-4對於AD皮膚組織中血管新生相關蛋白vWF表現量之影響 44
第四章、 討論 64
4.1 巨噬細胞在發炎中扮演的角色 65
4.2 發炎與氧化壓力的關係 66
4.3 發炎與血管新生的關係 67
4.4 發炎與異位性皮膚炎 70
4.4.1 WH-4對於BALB/c小鼠異位性皮膚炎之傷口外觀評分 70
4.4.2 WH-4對於BALB/c小鼠異位性皮膚炎之病理組織切片分析 71
4.4.3 異位性皮膚炎與Th1細胞及IFN-之關聯 72
4.4.4 巨噬細胞在異位性皮膚炎中扮演的角色 73
4.5 異位性皮膚炎與氧化壓力 75
4.6 異位性皮膚炎與血管新生之關係 76
第五章 未來展望 79
第六章 文獻參考 81

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