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系統識別號 U0026-1311201312230700
論文名稱(中文) 人類凝血酶調節素之類凝集素功能區對於血管損傷的抗發炎作用
論文名稱(英文) The Anti-inflammatory Effect of Thrombomodulin Lectin-like Domain upon Vascular Damage
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 1
出版年 102
研究生(中文) 林韋伶
研究生(英文) Wei-Ling Lin
電子信箱 s5897138@gmail.com
學號 S58971382
學位類別 博士
語文別 英文
論文頁數 85頁
口試委員 指導教授-吳華林
口試委員-施桂月
口試委員-張權發
口試委員-張堯
口試委員-林淑華
口試委員-吳佳慶
中文關鍵字 動脈硬化  發炎  白血球  路易士Y抗原  凝血酶調節素 
英文關鍵字 atherosclerosis  inflammation  leukocytes  Lewis Y antigen  thrombomodulin 
學科別分類
中文摘要 人類凝血酶調節素(thrombomodulin, TM)的胺基端類凝集素功能區(TM domain 1, TMD1)已知具有抗發炎功能。而我們先前發現醣類Lewisy (Ley)為重組TMD1(recombinant TMD1, rTMD1)的醣類配合基(ligand)。Ley被發現會表現於發炎組織中並且透過醣化在黏附分子上來調控細胞黏附。因此,我們研究是否rTMD1與Ley的作用會影響白血球黏附而抑制發炎反應。從實驗結果顯示,內皮細胞受到促發炎分子腫瘤壞死因子α (tumor necrosis factor- alpha, TNF-α)刺激後,細胞表面的Ley會增加,並且rTMD1會直接與之結合。在流體壓力下,Ley 促進白血球黏附的功能可以被rTMD1所抑制, 並且透過其與Ley結合來降低白血球黏附及穿越活化的內皮細胞。在小鼠實驗中,我們利用血管結紮及thioglycollate刺激腹膜炎的模式,發現給予rTMD1治療可降低白血球趨化(recruitment)到發炎組織。rTMD1也可以抑制載脂蛋白E剔除小鼠 (Apolipoprotein E-/-)動脈斑塊的產生及降低動脈粥狀化病變處巨噬細胞的侵入。利用發炎的血管組織,我們也偵測到高量表現的Ley及施打至動物體內的rTMD1。總結上述結果,rTMD1與內皮細胞上Ley的結合可以抑制Ley所調控的白血球黏附,進而有效抑制動脈硬化發生。此研究也提出了一個rTMD1透過跟其醣類配體Ley結合而抗發炎的新機制。
英文摘要 The N-terminal lectin-like domain (domain 1, D1) of thrombomodulin (TM) is known to have an anti-inflammatory function. We previously showed that recombinant TM domain 1 (rTMD1) interacts with a carbohydrate molecule, Lewis Y (Ley), which is found to be expressed on adhesion molecules and involves in cell adhesion. Here, we tested the effect of rTMD1/Ley interaction on leukocyte recruitment in inflammation. The expression of Ley on the surface of human umbilical vein endothelial cells was increased by tumor necrosis factor-α stimulation. Direct binding of rTMD1 to Ley on the cell surface was observed. rTMD1 inhibited Ley-mediated leukocyte adhesion on the Ley-immobilized flow chamber and activated endothelium under a shear flow. The following leukocyte transmigration to endothelium was also reduced by rTMD1 through binding Ley. In vivo, treatment of rTMD1 reduced leukocyte recruitment to the inflammatory sites in carotid ligation injury and thioglycollate-induced peritonitis. rTMD1 administration in apolipoprotein E-deficient mice effectively suppressed atherosclerotic plaque formation and macrophage infiltration in atherosclerotic lesions. Increased Ley expression, as well as administered rTMD1, was observed in inflamed vessels. In summary, rTMD1 suppressed vascular inflammation by inhibiting leukocyte recruitment to endothelium through attenuating Ley-mediated adhesion and further protected against atherosclerosis progression. The present study provides a mechanism showing that rTMD1 can inhibit inflammation by binding to its carbohydrate ligand Ley.
論文目次 Abstract...........................................3.
Chinese Abstract...................................4.
Acknowledgements...................................5.
Content Table......................................6.
Contents of Figure.................................7.
Abbreviation.......................................8.
Introduction......................................10.
Specific Aims.....................................20.
Materials and Methods.............................22.
Results...........................................41.
Discussion........................................47.
Impact and Significance...........................52.
Future Direction..................................52.
References........................................53.
Figures...........................................66.
Table.............................................77.
Appendix..........................................78.
Resume............................................85.
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