臺灣博碩士論文加值系統

肺臟是人體內和外界接觸面積最大的器官。肺臟的主要功能是氣體交換，提供氧氣給全身細胞所需維持生理功能的正常運作。一旦肺臟損傷，身體得不到充足的氧氣供應，細胞和器官就會因缺氧而逐漸失去功能，終至死亡。持續性肺部慢性損傷會造成細胞外基質(Extracellular matrix；ECM)和肺部結構的重組並趨向纖維化發展以及伴隨發炎反應的發生。正常狀況下的ECM組成包含膠原纖維(Collagen)、彈性纖維(Elastic Fiber)與結構性醣蛋白如纖連蛋白(Fibronectin)、層黏聯蛋白(Laminin)以及黏多醣多分子(Mucopolysaccharides)等，並受到基質金屬蛋白酶(Matrix metalloproteinases；MMPs)的調控。在小鼠實驗中已在肺部纖維化的統計中證實，MMPs的表現量與肺部的發炎反應有關；且MMPs參與纖維化嚴重程度的不同階段，MMPs能夠調節免疫、組織修復和組織重塑相關的過程，且在纖維化小鼠的肺部灌洗液中也偵測到高表現量的MMP9與MMP2。另一方面，一氧化碳釋放分子-2在生物體中能夠釋放少量一氧化碳；過去文獻說明，當組織受損會伴隨微環境缺氧的狀況形成並誘發相關的保護機制。第一型血紅素氧化酶是一個缺氧環境誘發蛋白質，被發現可以減緩肝臟纖維化的進程，但是第一型血紅素氧化酶與肺部纖維化的關係則較少被研究。因此我們著重於評估一氧化碳釋放分子-2藉由調控MMP9與MMP2表現量緩解纖維化的能力並探討相關的分子機制。我們以人類肺部纖維母細胞(WI-38細胞株)與博來黴素誘導的小鼠肺部纖維化模式為標的進行實驗研究。我們發現CORM-2 (Carbon Monoxide Releasing Molecule-2) 能調控NRF2、HIF-1與HO-1蛋白質表現增加，也可以隨著作用時間增加而減少MMP9與MMP2表現量。進一步將WI-38細胞前處理Ro31-8220、Gö-6976 (PKC抑制劑)、U0126 (ERK抑制劑)、SB202190 (p38 MAPK抑制劑)、SP600125 (JNK抑制劑)、N-acetylcysteine (ROS清除劑)、PP1 (Src抑制劑)都無法回復CORM-2減少MMP9與MMP2表現的情形。而前處理PI3-K抑制劑(LY294002)則能夠回復CORM-2對於MMP9與MMP2的作用。另外，藉由抑制HIF-1和HO-1或利用CO清除劑皆能夠降低CORM-2所造成MMP9與MMP2的減少；進一步實驗發現，CORM-2可以經由PI3-K調控HIF-1表現，進而增加HO-1基因表現導致細胞纖維化指標MMP9與MMP2的蛋白減少。而在小鼠模式方面，博來黴素誘發肺纖維化的小鼠實驗中，CORM-2也具有減少肺部組織膠原蛋白沉澱的能力，降低小鼠肺部白血球的聚集數量；再者，處理CORM-2也能夠減少MMP9和MMP2的mRNA表現。而在免疫組織染色的實驗結果也顯示CORM-2的處理可以增加小鼠肺部HIF-1、NRF-2與HO-1的蛋白質表現並減少博來黴素所導致的MMP9與MMP2的表現量。藉由這些細胞與動物模式實驗，CORM-2可以藉由PI3-K/HIF-1, NRF-2/HO-1路徑調控MMP9與MMP2表現量進而減少肺部纖維化的程度。

The main function of lung is oxygen exchange, which keeps the normal function of physiology via maintaining the oxygen concentration in the cells. Once injured and no enough oxygen supplement, the cells and organs lose functions that leads to the death. The persistent chronic lung injury results in the remodeling of extracellular matrix (ECM) and lung structure, companied with fibrosis and inflammation. The compositions of ECM in normal lung include collagen, elastic fiber and structure glycoproteins such as fibronectin, laminin, and mucopolysaccharides, regulated by matrix metalloproteinases (MMPs). Experimental models of fibrosis have shown the correlation between MMP expression and lung inflammation. The concentrations of MMP9 and MMP2 are high in the bronchoalveolar lavage of fibrotic mice, and participate in the fibrosis via regulating the immunity, tissue repair and remodeling. On the other hand, Carbon monoxide releasing Molecule-2 (CORM-2) promotes the repease of CO in organism. Previous literatures reveal that the injury of tissues promotes the protection mechanism with the hypoxia in microenvironment. Heme oxygenase-1 (HO-1) is a hypoxia-inducing protein and prevents progression of liver fibrosis. But, the correlation between HO-1 and lung fibrosis are less studied. We focus on evaluating the potentials of CORM-2 against lung fibrosis via regulating MMP9 and MMP2 expression and the relating molecular mechanisms. Human normal fibroblast (WI-38 cells) and bleomycin-stimulated lung fibrosis were used in this project. We found that CORM-2 (Carbon Monoxide Releasing Molecule-2) reduced MMP9 and MMP2 expression in WI-38 cells in a time dependent manner. Pretreatment inhibitors of PKC (Ro31-8220, Gö-6976), ERK (U0126), p38 MAPK (SB202190), JNK (SP600125), ROS (N-acetylcysteine) or Src (PP1) cannot reverse the decreased effects of CORM-2 on MMP9 and MMP2 expression. However, CORM-2-reduced MMP9 and MMP2 expression is attenuated by inhibitors of PI3K (LY294002). In addition, inhibiton of HIF-1 and HO-1 or scavenger of CO reverse the effects of CORM-2 on MMP9 and MMP2 expression. Further studies revel that CORM-2 increases HIF-1 expression via PI3-K, resulting in increased expression of HO-1 and decreased expression of fibrogenic marker, MMP9 and MMP2. On the aspect of in vivo model, CORM-2 reduced collagen deposition and leukocyte recruitments in lung tissues of bleomycin-treated mice. Treatment of COMR-2 reduces bleomycin-regulated MMP9 and MMP2 mRNA expression. Immunohistochemical assay further shows the increase of HIF-1, NRF-2 and HO-1 expression companied with decreased expression of MMP9 and MMP2 protein in CORM-2 treated mice. These studies reveal that CORM-2 facilitates the reduction of lung fibrosis via PI3-K/HIF-1, NRF-2/HO-1-down regulated MMP9 and MMP2 expression.

目錄 (Contents)

頁(page)
口試委員審定書
中文摘要 (Abstract in Chinese) i
英文摘要 (Abstract in English) iv
縮寫表 (Abbreviation) vii
致謝 (Acknowledgement) xii
目錄 (Contents) xiv
第一章 緒論 (Introduction) 1
第二章 研究目標 (Specific Aim) 34
第三章 實驗材料與方法設計 (Materials and Methods) 36
第四章 實驗結果 (Experimental Result) 47
第五章 討論 (Discussion) 54
第六章 結論 (Conclusion) 59
圖表 (Figures) 60
參考文獻 (Reference) 99

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