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研究生:蔡傑智
研究生(外文):Chieh-Chih Tsai
論文名稱:氧化性損傷在葛瑞夫玆氏眼病變的致病機轉中扮演之角色
論文名稱(外文):The Role of Oxidative Stress in the Pathogenesis of Graves' Ophthalmopathy
指導教授:魏耀揮魏耀揮引用關係許紋銘許紋銘引用關係邱士華邱士華引用關係
指導教授(外文):Yau-Huei WeiWen-Ming HsuShih-Hwa Chiou
學位類別:博士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:78
中文關鍵詞:葛瑞夫玆氏眼病變氧化性損傷纖維母細胞活性氧分子
外文關鍵詞:Graves’ ophthalmopathyoxidative stressfibroblastsreactive oxygen species
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葛瑞夫玆氏眼病變屬於一種免疫性的發炎性疾病,目前仍是葛瑞夫玆氏疾病中令人臨床上倍感困擾,且難以完全釐清的問題。形成這些臨床症狀的原因,主要源自眼球後方的眼外肌及脂肪結締組織在有限的眼窩空間中過度的增生所導致。許多臨床及基礎的研究學者由不同的角度,試圖找出葛瑞夫玆氏眼病變的致病原因,但目前仍無定論。近年來的研究顯示,其致病機轉可能是由複雜的內在因子與外在的環境因子共同影響疾病的發生。近期有許多研究發現氧化性損傷在葛瑞夫玆氏病及葛瑞夫玆氏眼病變的致病機轉中都扮演著重要的角色。Bednarek等學者發現過氧化氫、脂質過氧化物、超氧化物歧化酶及過氧化氫酶等在甲狀腺亢進患者的血液中的濃度會升高,當這些患者服用藥物使甲狀腺功能恢復正常後,這些氧化性損傷相關指數便會恢復正常,但在一些同時合併有眼病變的患者中,這些指數即使在他們的甲狀腺功能獲得控制後仍然持續偏高。這代表除了甲狀腺功能外,眼病變本身也可能造成氧化性損傷。然而這些活性氧化物質在葛瑞夫玆氏病中究竟扮演著何種的角色,仍有待進一步的研究來釐清。
在本研究中第一部分,我首先探討DNA氧化性損傷與葛瑞夫玆氏眼病變患者臨床疾病表現的活動性和嚴重程度的關係。研究結果顯示,葛瑞夫玆氏眼病變患者的尿液中有較高的DNA氧化性損傷指標: 8-氫氧-2’-去氧鳥糞核糖苷(8-OHdG),而且這種DNA氧化性損傷的程度與葛瑞夫玆氏眼病變的臨床活性呈現正相關。進一步分析發現在活性期的眼病變患者(臨床活性指數大於三)給予口服類固醇治療後,DNA氧化性損傷的程度及眼病變的臨床症狀都同時獲得改善。同時,我發現在葛瑞夫玆氏眼病變患者的尿液中,抽菸的患者遠比未抽菸的患者有較嚴重的DNA氧化性損傷指數,然而在健康對照組中無論是抽菸與否與其尿液中的8-OHdG高低並無統計上的相關。顯示抽菸除了已知是葛瑞夫玆氏眼病變的產生與惡化的危險因子外,更有可能使葛瑞夫玆氏眼病變患者的氧化性損傷更加惡化。以上的研究結果顯示DNA氧化性損傷在葛瑞夫玆氏眼病變的致病機轉中的確扮演著重要的角色;同時我發現尿液中的8-OHdG含量,在治療與追蹤葛瑞夫玆氏眼病變患者期間,可提供一非侵犯性、客觀且定量的生化指標。
在第二部分實驗,我進一步分析葛瑞夫玆氏眼病變患者培養出的眼窩纖維母細胞中的氧化壓力、活性氧分子及抗氧化酵素群在曝露於過氧化氫時的變化,並且和年紀相當的正常對照組的眼窩纖維母細胞作比較。結果顯示,葛瑞夫玆氏眼病變患者的眼窩維母細胞比正常細胞有較嚴重的DNA氧化性損傷和脂質過氧化傷害,同時存在有較高濃度的超氧化物陰離子及過氧化氫等活性氧化物,和較高活性的錳-超氧化物歧化酶,然而穀胱甘肽過氧化酶及還原態和氧化態穀胱甘肽的比值則較正常對照組低。超氧化物陰離子及過氧化氫已經被證實能夠刺激纖維母細胞的生長,然而纖維母細胞的增生正是葛瑞夫玆氏眼病變的主要病理特徵。另一方面,我發現以不同濃度的過氧化氫(100-400 μM)對兩組眼窩纖維母細胞同時刺激90分鐘後,這些細胞的生長受到不同程度的抑制。特別在以濃度200 μM過氧化氫處理後,患者這一組的眼窩纖維母細胞較正常組的眼窩纖維母細胞的存活比率開始有顯著的差異(患者組60%,正常對照組84%; p=0.003)。同時我發現以濃度200 μM過氧化氫處理兩組眼窩纖維母細胞後,葛瑞夫玆氏眼病變患者培養出的眼窩纖維母細胞原本就較嚴重的的脂質過氧化傷害及較高濃度的過氧化氫與錳-超氧化物歧化酶變得更明顯,而且比正常對照組的反應更加劇烈。此外,經過200 μM過氧化氫處理後,患者組原本就較低的過氧化氫酶、穀胱甘肽過氧化酶及還原態與氧化態穀胱甘肽之比值變得更低,而且比起正常對照組降低的比例更為顯著。 由第二部分實驗結果,我推論葛瑞夫玆氏眼病變患者培養出的眼窩纖維母細胞因其抗氧化酵素的不平衡,對外在氧化性壓力較敏感,因此容易累積過多的活性氧分子。許多研究顯示低濃度之活性氧分子會刺激纖維母細胞的增生,這也正是葛瑞夫玆氏眼病變的重要特徵;當活性氧分子累積到高濃度時,則會進而造成嚴重的氧化性傷害。這也呼應我第一部分研究的發現,葛瑞夫玆氏眼病變患者的尿液中有較嚴重的DNA氧化性損傷。因此葛瑞夫玆氏眼病變患者與正常對照組中纖維母細胞對抗外在氧化壓力能力表現的差異,可能在這個疾病的致病機轉中扮演著重要的角色。我在葛瑞夫玆氏眼病變患者及其眼窩纖維母細胞中氧化性損傷、活性氧化物及抗氧化酵素的研究成果,對於進一步了解葛瑞夫玆氏眼病變的致病機轉及發展新的治療策略將有很大的幫助。
Graves’ ophthalmopathy (GO), an inflammatory disorder of autoimmune background, represents a clinically vexing and poorly understood component of Graves’ disease. The clinical manifestations of GO involve a combination of increased orbital fat connective tissues and extraocular muscle volume within the limited orbital space. Many ongoing biomedical science and clinical research have been done to unravel the pathogenesis of GO. However, a clear and indisputable mechanism has not been established. It may involve a complex interplay between endogenous and environmental factors. Accumulating evidence has shown that oxidative stress plays an important role in the pathogenesis of Graves’ disease and GO. Recent studies showed that the tissue levels of hydrogen peroxide (H2O2) and lipid peroxides and plasma levels of superoxide dismutase and catalase are increased in patients with Graves’ disease. It is noteworthy that the hyperthyroid state could be normalized with the antithyroid agent except those with infiltrative ophthalmopathy. This implies that apart from the influence of the thyroid metabolic status, ophthalmopathy itself may also trigger changes in the ROS levels in blood. However, the contribution of ROS to the ocular changes of Graves’ disease has remained poorly understood.

To investigate whether oxidative stress plays a role in the pathogenesis of GO, I investigated the relationship between the urinary level of 8-hydroxy 2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, in GO patients and their clinical evolution in the first part of this study. I observed that urinary levels of 8-OHdG were increased in GO patients as compared to those of normal controls, and this biomarker was correlated with the disease severity. In addition, the urinary levels of 8-OHdG in patients with active GO could be reduced after treatment with systemic steroids, accompanied by a decrease of clinical evolution of GO. Furthermore, the smokers had significant higher urinary 8-OHdG than did never-smokers in GO patients, but not in healthy controls. This finding indicates that smoking contributes to not only the severity of eye disease but also an increase of oxidative DNA damage in GO patients, further supporting that cessation of smoking is important for the management of Graves' ophthalmopathy. These results suggest that oxidative stress may play a role in the pathogenesis of GO, at least in perpetuating the ongoing oxidative damage to DNA. In addition, urinary 8-OHdG can serve as not only a noninvasive biomarker of oxidative stress in GO patients but also an objective parameter in the follow-up of patients receiving the immunosuppressive treatment.

In the second part of the study, the role of oxidative stress in cultured orbital fibroblasts from patients with GO was further investigated. The results revealed that the levels of 8-OHdG, malondialdehyde (MDA), the intracellular levels of superoxide anions, H2O2, and the Mn-superoxide dismutase (Mn-SOD) activity of GO fibroblasts were significantly increased, whereas the activity of glutathione peroxidase (GPx) and the GSH/GSSG ratio were dramatically decreased as compared with those of age-matched controls. We also evaluated the change of oxidative stress of cultured orbital fibroblasts in response to H2O2 treatment. The viability of normal and GO fibroblasts was decreased to 84% and 60%, respectively, after treatment with 200 μM H2O2. After treatment, the amplitudes of increase in the MDA, intracellular levels of H2O2 and Mn-SOD activity were significantly higher in GO fibroblasts compared with those of age-matched controls. Moreover, H2O2 treatment led to a marked decrease of catalase activity, GPx activity, and GSH/GSSG ratio in GO fibroblasts as compared to age-matched controls. The data suggest that the susceptibility to H2O2 of GO orbital fibroblasts due to the imbalance of antioxidant enzymes activities may further lead to the accumulation of ROS. Previous studies have demonstrated that low concentrations of ROS especially superoxide anions and H2O2 could induce cellular proliferation of fibroblasts, which is a key pathological feature in the overt expression of ophthalmopathy in GO patients. However, at higher concentrations ROS can cause subsequent ROS- mediated oxidative stress and oxidative damage. These GO orbital fibroblasts exhibited potentially important differences in their phenotypes that may play an important role in the pathogenesis of GO. My findings are of great importance for a better understanding of the molecular basis of ROS metabolism and antioxidant defense in the pathogenesis of GO, and thus provide a potential avenue for the development of novel strategy for the treatment of GO.
一、中文摘要 ………………………………………………… 2
二、英文摘要 ………………………………………………… 6
三、英文縮寫表 ……………………………………………… 9
四、緒論
1. Graves’ ophthalmopathy ……………………………… 11
2. Oxidative stress and Graves’ disease ………… 14
3. Oxidative stress and Graves’ ophthalmopathy … 15
4. Rationale of the study………………………………… 16
五、研究設計、方法與材料 ………………………………… 18
六、結果 ……………………………………………………… 27
七、討論 ……………………………………………………… 32
八、展望 ……………………………………………………… 41
九、參考文獻 ………………………………………………… 43
十、圖表 ……………………………………………………… 58
十一、附錄:個人在博士班修業期間所發表之相關論文 … 75
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