皮膚是一種物理與化學屏障用來對抗病原體的入侵。此外，皮膚在分泌作用、溫度平衡、排泄作用、調節呼吸與皮膚感官都扮演重要的角色。因此，當皮膚受損時無法接受適當治療，將會導致擾人的慢性疾病發生，將會產生更多的醫療負擔及長期的患者壓力。在本研究中，我們專注於兩種皮膚疾病，燙傷與異位性皮膚炎(atopic dermatitis, AD)。這兩種都屬於常見的高好發率疾病。不幸的是，沒有任何藥物可以有效的治療燙傷與AD且不帶有副作用。因此，當務之急是開發新的藥物去治療這些疾病。海洋資源的多樣性使得海洋化合物相較於陸地植物更能產生獨特的生物活性。因此，海洋資源中可能存有治療燙傷與AD的海洋化合物。海洋化合物EWH是從海洋柳珊瑚提取。在我們先前的研究中發現，EWH具有減緩促發炎細胞因子的發炎作用。在我們的研究中，使用了離體的細胞傷口癒合模型來評估EWH是否可以促進內皮細胞EA Hy92與纖維母細胞Hs68的遷移。此外，透過斑馬魚模式發現EWH可以增加血管新生。接著，我們發現EWH在大鼠燙傷模式中促進傷口癒合且治療效果比臨床用藥的磺胺嘧啶銀更好。在另一部份，EWH可能會緩解AD的病理現象。總結，EWH未來可以發展為一個潛力藥物來針對燙傷及AD的治療。

Skin is a mechanical and a chemical barrier against the invasion of pathogens. In addition, skin also plays an important role in the secretion, temperature homeostasis, excretion, respiration and skin sensory. Therefore, when skin damage doesn’t receive proper treatments, it will result in annoying chronic diseases. In this study, we focus on two different dermatologic disorders which are burn injury and atopic dermatitis. Both of two diseases are very common and high prevalence. Unfortunately, there are no drugs that could effectively treat burn injury and AD without side effects. Thence, developing new drugs for these diseases is imperative. The diversity of marine resources improves marine drugs to generate different bioactivities unlike terrestrial plants. For this reason, ocean may exist a promising hope to treat burn injury and AD. Marine compound (EWH) was extracted from the sea gorgonian. Our previous study also found that EWH has anti-inflammatory effects for relieving rheumatoid arthritis and reducing the pro-inflammatory cytokines. In our study, we used in vitro cell wound healing model to assess whether EWH could promote EA hy 926 endothelial cells and fibroblasts Hs68 migration. Besides, EWH could enhance angiogenesis by using zebrafish model. Next, we found that EWH could improve wound healing of burn injury by rat model and the therapeutic effect is better than silver sulfadiazine cream which is the clinical drug. On the other part, EWH may alleviate the symptoms of AD and reduce the AD score. In a word, EWH may have potential to become a promising drug to treat burn injury and AD in the future.

論文審定書 i
誌謝 ii
中文摘要 iii
ABSTRACT iv
目錄 v
圖目錄 ix
表目錄 xiii
縮寫表 xiv
第一部分:海洋天然物於燒燙傷之治療 1
第壹章、前言 2
海洋藥物資源 2
海洋藥物研發概況 2
燙傷流行病學統計 9
現今治療燙傷之臨床藥物 10
皮膚組織及燙傷癒合機制 11
發炎反應與傷口癒合關係 14
血管新生與傷口癒合關係 16
傷口癒合研究之離體與活體斑馬魚，老鼠模式 17
研究目的與動機 19
第貳章、材料與方法 21
離體細胞實驗 21
活體斑馬魚實驗 22
活體動物實驗 23
第參章、實驗結果 28
海洋化合物對於人類臍靜脈內皮細胞株EA.hy 926之存活率影響 28
海洋化合物對於EA.hy 926細胞遷移(cell migration)能力之影響 28
海洋化合物對於人類上皮纖維母細胞株Hs68之存活率影響 29
海洋化合物對於Hs68細胞遷移(cell migration)能力之影響 29
海洋化合物對基因轉殖Tg(fli 1:EGFP)螢光斑馬魚仔魚之體節間血管(intersegmental vessel, ISV)生成之影響 30
海洋化合物對基因轉殖Tg(fli 1:EGFP)血管螢光斑馬仔魚之尾鰭損傷後肉 芽組織之影響 30
海洋化合物對於大鼠燙傷傷口癒合之影響 30
海洋化合物對於燙傷傷口組織的病理檢驗 31
海洋化合物對於發炎因子iNOS表現量之影響 32
海洋化合物對於發炎因子COX-2表現量之影響 33
海洋化合物對於傷口發炎因子CD11b數量之影響 33
海洋化合物對於促進血管新生的生長因子VEGF-a表現量之影響 33
海洋化合物對於傷口癒合之生長因子vWF表現量之影響 34
海洋化合物對於傷口癒合之生長因子Hsp90表現量之影響 34
第肆章、討論 52
海洋化合物的促進血管新生作用 52
海洋化合物對於傷口癒合之促進作用 53
海洋化合物對於活體斑馬魚血管新生作用之影響 54
海洋化合物對於燙傷傷口癒合之效用 55
海洋化合物在傷口癒合中之作用機轉 56
血管新生因子在傷口癒合中的作用機轉 58
Hsp90對於傷口癒合之可能作用 59
EWH對於燙傷治療之機轉 60
第五章、結論 60
第二部分:海洋天然物於異位性皮膚炎之影響 62
第壹章、 前言 63
異位性皮膚炎流行病學之介紹 63
異位性皮膚炎現今臨床治療方法 63
異位性皮膚炎致病機轉 65
異位性皮膚炎與巨噬細胞之關係 66
異位性皮膚炎與血管新生之關係 67
異位性皮膚炎藥物開發模式 68
研究目的與動機 69
第貳章、材料與方法 70
活體動物實驗 70
動物照護 70
動物誘發模式 70
傷口給藥 71
傷口觀察 71
實驗組別 71
皮膚樣品收集與組織學分析 72
甲苯胺藍染色 72
免疫組織化學染色 73
西方墨點法組織前處理方法 74
西方點墨法(Western blot) 74
實驗數據分析 75
第參章、實驗結果 75
海洋化合物對於Wistar大鼠異位性皮膚炎傷口之外觀影響 75
海洋化合物對於Wistar大鼠異位性皮膚炎組織之影響 75
海洋化合物對於Wistar大鼠異位性皮膚炎組織中肥大細胞表現量之影響 76
海洋化合物對於發炎因子IL-17a表現量之影響 76
海洋化合物對於皮膚發炎因子iNOS、COX-2表現量之影響 77
海洋化合物對於Wistar大鼠異位性皮膚炎組織中促血管生長因子VEGF-a 表現量之影響 77
海洋化合物對於Wistar大鼠異位性皮膚炎組織中促血管生長因子HO-1 表現量之影響 78
海洋化合物對於Wistar大鼠異位性皮膚炎組織中CTGF表現量之影響 78
海洋化合物對於BALB/c小鼠異位性皮膚炎之外觀影響 79
海洋化合物對於BALB/c小鼠異位性皮膚炎皮膚組織的病理影響 79
海洋化合物對於BALB/c小鼠異位性皮膚炎組織中肥大細胞浸潤之影響 80
海洋化合物對於BALB/c小鼠異位性皮膚炎組織中發炎前驅因子 80
(一) iNOS表現量之影響 80
(二)COX-2表現量之影響 81
(三)CD11b表現量之影響 81
(四)IL-17a表現量之影響 81
海洋化合物對於BALB/c小鼠異位性皮膚炎組織中的血管新生因子之影響 82
(一)VEGF-a表現量之影響 82
(二)HO-1表現之影響 82
(三)vWF表現之影響 83
第肆章、討論 110
異位性皮膚炎與巨噬細胞之關係 110
異位性皮膚炎與血管新生之關係 111
海洋化合物於大鼠異位性皮膚炎模式之治療效果 111
海洋化合物對於BALB/c小鼠異位性皮膚炎之治療效果 113
肥大細胞於異位性皮膚炎扮演的角色 114
巨噬細胞在異位性皮膚炎中所扮演的角色 115
血管新生在異位性皮膚炎中所扮演的角色 117
EWH對於異位性皮膚炎治療之轉機 119
第五章、結論 120
參考文獻 121

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