糖尿病特徵是血漿葡萄糖濃度增高及併發皮膚感染率增加，免疫反應的改變被認為是造成此併發症的可能原因。在高糖環境下，表皮角質細胞產生的抗菌物質減少，包括透過糖化終產物的產生而抑制了p38MAPK訊息傳遞使得乙型防禦素-3 (BD3)產量減少，抑制Staphylococcus aureus 的能力降低，因而容易出現糖尿病的皮膚感染。另外，角質細胞在高糖環境下亦有乙型防禦素-2 (BD2)表現減少情形，同樣是透過糖化終產物而抑制了pSTAT-1訊息傳遞所致。糖尿病傷口除了角質細胞本身受高糖環境影響外，也有和發炎細胞間交互作用的間接影響導致癒合受損。角質細胞在高糖環境下透過活性氧化物種的產生而刺激EGFR-ERK路徑，使得白介素-8 (IL-8)產量增加，因而吸引更多中性球至傷口處，當抑制中性球功能後，即可改善糖尿病鼠的傷口癒合。此外，單核球在高糖培養後，因為白介素-22 (IL-22)產量減少而降低了促進角質細胞移動的能力。整體而言，高糖對角質細胞功能的直接或間接影響都表現出糖尿病傷口癒合不良的情形，若能針對潛在的原因作改善，不失為治療的策略。

Diabetes mellitus is characterized by elevated plasma glucose and increased rate of skin infection. Altered immune responses have been suggested to contribute to this prevalent complication. High glucose treatment reduced human β-defensin-3 (hBD3) expression of cultured keratinocytes. This pathogenic process involved inhibition of p38MAPK signaling, an event that resulted from increased formation of advanced glycation end product and showed worse anti-Staphylococcus aureus activity. In addition, high-glucose cultivated keratinocytes expressed reduced levels of human β-defensin-2 (hBD2) and pSTAT-1. Besides the impact on keratinocyte cultured under high glucose, the suboptimal interaction between keratinocytes and inflammatory cells also contributed to impaired diabetic wound healing. High-glucose environment enhanced interleukin (IL)-8 production via EGFR-ERK pathway in a ROS-dependent manner in keratinocytes. Treating diabetic rats with neutrophil inhibitor improved the healing. On the other hands, high glucose cultivated monocytes have significantly reduced production of IL-22, a molecule that is responsible for promoting keratinocyte migration. In summary, high glucose environment impared keratinocyte function directly or indirectly that contributed to impaired diabetic wound healing, and focusing on these defects will present a therapeutic approach to promote diabetic healing.

論文審定書……………………………………………………………………………i
致謝……………………………………………………………………………………ii
中文摘要………………………………………………………………………………iii
英文摘要………………………………………………………………………………iv
目錄……………………………………………………………………………………v
圖次……………………………………………………………………………………viii
表次……………………………………………………………………………………xii
縮寫表…………………………………………………………………………………xiii
第一章 緒論…………………………………………………………………………….1
第一節 前言…………………………………………………………..……………...1
第二節 文獻探討……………………………………………………………..……...1
第二章 高糖環境在人類角質細胞抑制了p38MAPK的訊息傳遞並減少β-defensin-3的表現………………………………………………………………………….8
第一節 摘要………………………………………………………………………….8
第二節 研究背景……………………………………………………………..……...8
第三節 實驗方法………………………………………………………………….....9
第四節 實驗結果………………………………………………………………..….14
第五節 討論………………………………………………………………..……….17
第三章 高糖環境降低人類角質細胞β-defensin-2的表現…………………………..37
第一節 摘要………………………………………………………………………...37
第二節 研究背景…………………………………………………………..……….37
第三節 實驗方法……………………………………………………………..…….38
第四節 實驗結果…………………………………………………………..……….40
第五節 討論…………………………………………………………………..…….41
第四章 高糖環境促進角質細胞的氧化壓力並增加IL-8的釋出…………………..53
第一節 摘要…………………………………………………………………...……53
第二節 研究背景…………………………………………………………..……….53
第三節 實驗方法……………………………………………………………..…….54
第四節 實驗結果…………………………………………………………..……….58
第五節 討論……………………………………………………………………..….60
第五章 高糖培養之周邊血單核球透過降低IL-22表現而使角質細胞功能受損…81
第一節 摘要……………………………………………………………………..….81
第二節 研究背景………………………………………………………………..….81
第三節 實驗方法………………………………………………………….…….….82
第四節 實驗結果………………………………………………………………..….85
第五節 討論…………………………………………………………………..…….87
第六章 結論………………………………………………………………………….102
參考文獻……………………………………………………………………………105
附錄一 免疫組織化學染色使用之抗體…………………………………………….118
附錄二 西方墨點法使用之抗體…………………………………………………….119
附錄三 即時聚合酶鏈鎖反應使用之primer序列………………………………..…120
附錄四 角質細胞分化之蛋白質標記……………………………………………….121
附錄五 本論文已發表之文章原文……………..…………………….……………..122

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