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研究生:黃國棟
研究生(外文):Kuo-Tong Huang
論文名稱:探討Dipyridamole在Anti-Thy-1抗體引發腎絲球腎炎動物模式中的抗發炎功能
論文名稱(外文):The anti-inflammatory effects of dipyridamole in anti-Thy-1 antibody induced Glomerulonephritis
指導教授:李宏謨李宏謨引用關係
指導教授(外文):Horng-Mo Lee
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學檢驗生物技術學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:78
中文關鍵詞:腎絲球腎炎抗發炎
外文關鍵詞:dipyridamoleanti-inflammatoryGlomerulonephritis
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Anti-thy-1 抗體所引發的腎絲球腎炎,是一種常被引用來研究腎環門間質細胞( Mesangial cell )增生性腎絲球腎炎的動物模式。Dipyridamole是一種phosphodiesterase抑制劑,臨床上曾被用來治療由絲球體腎炎所引起的蛋白尿。然而,Dipyridamole於臨床上的治療機制目前尚未完全明瞭。由實驗室先前的研究顯示;發現到,施打anti-Thy-1抗體所引發的急性腎絲球腎炎,其症狀會出現明顯蛋白尿、ED(+)巨噬細胞移行、浸潤、及中度的PCNA(+)細胞增生。以上這些症狀經由Dipyridamole( 5mg/kg )治療的大鼠實驗可明顯觀察到抑制情形。TGF-β對於調控細胞外基質-collegen、fibronectin的分泌具重要的關鍵。我們也測試了Dipyridamole對於TGF-β表現和細胞間質增生、堆積的抑制,是否有相同的效果。由PAS score增加顯示;經由施打anti-Thy-1抗體所引發的少量腎絲球TGF-β增生和細胞基質堆積,以Dipyridamole治療後,發現在腎絲球PAS score和TGF-β表現有明顯的減少。 Heme-oxygenase-1(HO-1)是一種生理性壓力指標,Thy-1抗體所引起的HO-1表現會增加,在Dipyridamole治療後也會受到抑制。Osteopontin(OPN) 是一種bone sialoprotein,也曾被報導和腎臟纖維化有關。我們研究了OPN 在Thy-1抗體引發的腎炎所扮演的功能,發現OPN是一種組織的組成物質,於正常腎臟的腎小管、鮑氏囊體、及亨利氏環均有存在。施打anti-Thy-1抗體後於腎小管位置OPN有顯著的增加,但在絲球體卻沒有發現。所以,OPN不是和Thy-1產生的腎炎及腎纖維化有相關性。本實驗所使用Dipyridamole治療由Thy-1引起的OPN表現,於腎小管位置有發現受到抑制,但於腎小球沒有發現。綜合以上的報告,Dipyridamole 治療由anti-Thy-1引起的腎絲球腎炎蛋白尿,具有抑制的功效。
Anti-thy1 antibody-induced glomerular nephritis is a well established animal model for Mesangial cell proliferative glomeruli nephritis. Dipyridamole is a phosphodiesterase inhibitor, which has been shown to reduce GN-associated proteinurea. However, the detail mechanisms by which dipyridamole exert its therapeutic effects has not been elucidated. In the present study, we investigate the effect of dipyridamole on anti-thy1 -induced glomerular nephritis. We found that injection of anti-thy1 antibody resulted in acute glomerular nephritis (GN), characterized with massive proteinurea, increased of ED(+) macrophage infiltration and moderate PCNA(+) cell proliferation. These effects were all inhibited by treatment of rats with dipyridamole (5mg/Kg). TGF-β?浵as been shown to play an important role in extracellular matrix secretion. We next examined whether treatment of dipyridamole exerted beneficial effects on glomerular TGF-β expression and extracellular matrix accumulation. Injection of anti-thy1 antibody resulted in a mild increase of glomerular TGF-β and extracellular matrix accumulation as revealed by increased PAS score. Treatment of GN rats with dipyridamole significantly reduced the PAS score and TGF-β expresseion levels in glomeruli. Thy-1 antibody induced the expression of hem-oxygenase-1 (HO-1), a stress-induced marker, and the HO-1 induction was inhibited by treatment of rats with dipyridamole. Osteopontin, a bone sialoprotein, has been linked to renal fibrosis. I next investigate whether osteopontin (OPN) plays a role in anti Thy1 Ab-induced GN. OPN was constitutively expressed in tubules, Bowman’s capsule, and glomerular tuft of normal kidney. Injection of anti-thy1 antibody increased OPN expression in renal tubules but not in glomeruli, suggesting OPN was not associated with thy1-induced GN and subsequent renal fibrosis. Treatment of cells with dipyridamole reduced thy1-antibody stimulated OPN expression in renal tubule, but has little effect on glomerular OPN expression. Taken together, our results demonstrated that dipyridamole exhibited beneficial effects on thy-1 antibody induced GN.
中 文 摘 要 I
英 文 摘 要 III
縮 寫 表 IX
第 一 章 緒 論 1
1-2 Dipyridamole 的作用 : 11
1-2.1 P D E I ( phosphodiesterase inhibitor ) 與疾病的關係 : 14
1-3 : 血紅素氧化酵素 (Heme oxygenases,HOs) 15
1-3-1 : HO 之介紹 15
1-3-2 : HO-1的特性及生理作用 16
1-4 :活化性氧分子(Reactive oxygen species;ROS)之介紹 : 17
1-5: 相 關 之 文 獻 回 顧 18
1-6: 研 究 動 機 與 目 的 : 20
第二章 實驗材料與方法 22
2-1、實驗藥品 22
2-2、常用儀器 24
2-3、常用溶液 25
2-4實 驗 方 法 : 26
2-4.1 : Anti-Thy-1 Nephritis 動物模式的建立 : 26
2-4.2 :絲球體蛋白質測定(西方點墨法): 28
2-4.3 : 蛋白尿及其他生化檢驗 : 29
2-4.4 : H&E , PAS staining : 29
2-4.5:Immunohistochemistry staining : Anti-ED-1 staining 29
2-5 統計分析 : 30



第三章 實驗結果: 31
( 一 ) Dipyridamole 治療蛋白尿的功能: 31
( 二 )Dipyridamole 治療組織學的變化: 32
( 三 ) Dipyridamole對於發炎細胞ED-1(+)的功效: 32
( 四 ) Dipyridamole對PCNA(+)cell的功效: 33
( 五 ) Dipyridamole 與 Osteopontin的調控: 33
( 六 ) Dipyridamo對Heme oxygenase-1的調控: 34
( 七 ) Dipyridamole 調控TGF-beta的表現: 35
第四章 討 論 37
參 考 文 獻 42
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