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研究生:方怡謨
研究生(外文):I-Mo Fang
論文名稱:老年性黃斑部病變預防與治療之臨床與基礎相關研究
論文名稱(外文):Clinical and Basic Research of the Prevention and Treatment for Aged-Related Macular Degeneration
指導教授:陳慕師陳慕師引用關係林欽塘林欽塘引用關係楊長豪楊長豪引用關係
指導教授(外文):Muh-Shy ChenChin-Tarng LinChang-Hao Yang
學位類別:博士
校院名稱:國立臺灣大學
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:中文
論文頁數:172
中文關鍵詞:老年性黃斑部病變亞麻油酸脂肪酸一氧化氮聚合酶前列腺合成酵素葉黃素視網膜色素細胞移植組織胞漿素原活化劑
外文關鍵詞:age-related macular degenerationlinoleic acidfatty acidiNOSCOX-2luteinretinal pigment epithelial transplantationtissue plasminogen activator
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本論文的宗旨為老年性黃斑部病變預防與治療之臨床與基礎相關研究。論文主要分為三大部分,第一部分是關於老年性黃斑部病變的預防,可分為兩個小節,第一小節主要是探討亞麻油酸誘發老年性黃斑部病變脈絡膜新生血管可能的分子機轉與訊息傳導途徑。重點在於探究亞麻油酸能否刺激視網膜色素細胞表現促脈絡膜新生血管的介質: inducible nitric oxide synthase (iNOS) 與cyclooxygenase (COX)-2,並進ㄧ歩探討轉錄因子NF-kB調控這些介質可能的機轉。第二小節主要是利用第一小節所建立之分子機轉為模式,比較飲食中的脂肪酸,包括:飽和脂肪酸、單元不飽和脂肪酸與多元不飽和脂肪酸刺激視網膜色素細胞表現iNOS與COX-2的能力,並探討葉黃素能否抑制脂肪酸促進iNOS與COX-2表現的作用與可能的調控機轉,以期由分子生物的觀點來探討飲食中哪種脂肪酸容易誘發產生脈絡膜新生血管,作為調整飲食成分以預防老年性黃斑部病變的參考。此外我們也提出另一個葉黃素治療老年性黃斑部病變脈絡膜新生血管的分子機轉。第二部分是老年性黃斑部病變治療的基礎研究。以手術切除絡膜新生血管膜手術來治療脈絡膜新生血管時,常需要合併施行視網膜色素細胞移植,以避免脈絡膜與視神經產生續發性萎縮。本論文第二部分主要是探討integrinα6β4在視網膜色素細胞的表現與細胞貼附所扮演的角色,進一步研究增加移植細胞上integrinα6β4的表現能否增加移植細胞在Bruch''s membrane的貼附率,以增加視網膜色素細胞移植的成功率。第三部分是關於老年性黃斑部病變治療的臨床研究,主要是探討利用玻璃體內注射組織胞漿素原活化劑(tissue plasminogen activator, t-PA)來協助氣體位移(pneumatic displacement)黃斑部下出血的治療效果與使用的時機。
在台灣與西方已開發國家,老年性黃斑部病變是50歲以上成人失明的主因之ㄧ。而肇因於老年性黃斑部病變所導致嚴重視力喪失的病例中,絕大部份是因脈絡膜新生血管所引起的。飲食是老年性黃斑部病變的危險因子之ㄧ,因此"調整飲食的成分"是預防老年性黃斑部病變最重要的方式之ㄧ。流行病學研究顯示食物中攝取高植物性脂肪、高多元不飽和脂肪酸容易引發老年性黃斑部病變,尤其是高亞麻油酸(linoleic acid)的攝取。只有在低亞麻油酸攝取者,高魚脂肪及高w-3脂肪酸的攝取才具有預防老年性黃斑部病變的作用。由於亞麻油酸是一種必需脂肪酸,也是日常食物中重要的成分。因此本論文中的第一部分第一個小節,主要是從分子生物的觀點來探討亞麻油酸誘發老年性黃斑部病變脈絡膜新生血管可能的致病機轉與訊息傳導途徑。我們提出一個假說:亞麻油酸是否能刺激視網膜色素細胞,經由活化NF-B的表現而產生促脈絡膜新生血管的介質iNOS、COX-2、prostaglandin E2 (PGE2)與 nitric oxide (NO)。爲了證明此假說,我們以不同濃度的亞麻油酸刺激人類視網膜色素細胞株(ARPE-19)。利用RT-PCR及Western blot分析,我們發現ARPE-19細胞在亞麻油酸的刺激之下,iNOS與COX-2 mRNA與蛋白質的表現,會隨著亞麻油酸的濃度越高表現越多。利用enzyme-link immunosorbent assay (ELISA) 分析,我們發現ARPE-19細胞在亞麻油酸刺激之下,也會促進NO 與PGE2的產生。利用electrophoretic mobility shift assay (EMSA)分析,我們發現亞麻油酸能刺激ARPE-19細胞增加細胞核中NF-kB與DNA上NF-B結合位置的結合能力,代表亞麻油酸能活化ARPE-19細胞中的轉錄因子NF-kB。利用RT-PCR和ELISA分析,我們發現NF-kB抑制劑—PDTC 能抑制亞麻油酸促進ARPE-19細胞表現iNOS 與COX-2 mRNA的作用,代表NF-kB參與調控亞麻油酸刺激ARPE-19細胞表現iNOS 與COX-2的作用。利用Western blot分析,我們發現亞麻油酸刺激ARPE-19細胞會促進細胞質中IkB的分解,代表亞麻油酸活化NF-kB的作用是經由促進細胞質中IkB的分解,使NF-kB活化,以調控COX-2與iNOS基因。從Western blot分析,我們發現亞麻油酸刺激ARPE-19細胞會促進p42/p44 MAPK蛋白質的磷酸化,增加phosphated p42/p44 MAPK蛋白質的合成。相反的,亞麻油酸並不會增加phosphated p38 MAPK與phosphated JNK蛋白質的合成。利用EMSA分析,我們發現p42/p44 MAPK抑制劑PD98059會抑制亞麻油酸促進NF-kB與DNA上NF-kB結合位置結合的作用,而p38 MAPK抑制劑 SB20358並不具有抑制NF-kB活化的作用,這代表亞麻油酸活化NF-kB的作用是經由活化p42/p44 MAPK路徑,而非經由p38 MAPK或JNK路徑。綜合上述的結果,我們提出一個亞麻油酸促進老年性黃斑部病變脈絡膜新生血管可能的分子機轉:亞麻油酸經由活化視網膜色素細胞內p42/p44 MAPK路徑,促進NF-kB抑制蛋白IkB的分解,使NF-kB能活化而轉位到細胞核中,增加NF-kB與promoter上NF-kB結合位置的結合,進而促進COX-2 與iNOS mRNA的表現與蛋白質的合成,並進而催化產生PGE2 與NO。藉由COX-2 、iNOS、PGE2 與NO引發發炎反應與促新生血管的作用,而產生脈絡膜新生血管。根據這個機轉,我們支持之前流行病學研究的概念:高亞麻油酸食物的攝取容易引發老年性黃斑部病變。因此,在臨床上我們可提醒民眾盡量減少含亞麻油酸的食物,如:大豆油、葵花油、紅花油、花生油、菜籽油..等的攝取,以預防老年性黃斑部病變。
本論文第一部分第二小節主要是根據上ㄧ小節所建立的模式,探討各種脂肪酸刺激視網膜色素細胞產生與老年性黃斑部病變脈絡膜新生血管形成有關之iNOS,COX-2的能力。希望能以分子生物的觀點,探討飲食中哪一類脂肪酸容易導致老年性黃斑部病變。本研究所採用的脂肪酸是相同碳鏈長度,但飽合程度不同之18個碳鏈的脂肪酸,包括:硬脂酸(stearic acid, SA, 18:0)、油酸(oleic acid, OA, 18-1)、亞麻油酸(linoleic acid, LA, 18-2), 次亞麻油酸(linolenic acid, LnA,18-3)。這些脂肪酸都是飲食中常見的脂肪酸。我們之所以挑選相同碳鏈的脂肪酸來進行研究,主要是希望能避免不同碳鏈長度的影響,以單獨測出不飽和程度(degree of unsaturation)對於細胞產生iNOS與COX-2的影響。從RT-PCR與Western blot分析,我們發現ARPE-19細胞在不飽和脂肪酸,包括:油酸、亞麻油酸、次亞麻油酸刺激之下,COX-2,iNOS mRNA的表現與蛋白質的合成,會隨刺激濃度的增加而增加。相反的,飽和脂肪酸的硬脂酸並無法刺激細胞促進COX-2,iNOS mRNA的表現與蛋白質的合成。在這些脂肪酸中,以含有兩個不飽合鍵的亞麻油酸,刺激誘發COX-2與iNOS mRNA的表現與蛋白質的合成的能力最強。同樣地,從ELISA分析,我們發現不飽和脂肪酸也會刺激ARPE-19細胞促進NO與PGE2的合成;而飽和脂肪酸的硬脂酸也無法刺激細胞促進NO與PGE2的合成。其中,也是以亞麻油酸刺激促進NO與PGE2合成的能力最強。從EMSA分析,我們發現不飽和脂肪酸,包括:油酸、亞麻油酸、次亞麻油酸會增加細胞核中NF-kB與DNA的結合能力,而飽和脂肪酸的硬脂酸並無法增加細胞核中NF-kB與DNA的結合能力。其中,也是以亞麻油酸增加NF-kB結合能力的作用最顯著。從NF-kB promoter reporter分析,我們發現不飽和脂肪酸包括:油酸、亞麻油酸、次亞麻油酸,也會刺激視網膜色素細胞,增加NF-kB所調控基因的轉錄作用,而飽和脂肪酸的硬脂酸無法刺激促進NF-kB所調控基因的轉錄作用。其中,也是以亞麻油酸增加NF-kB所調控基因的轉錄作用最顯著。從RT-PCR與Western blot分析,我們發現NF-kB抑制劑PDTC有效抑制不飽和脂肪酸刺激視網膜色素細胞促進COX-2與iNOS mRNA表現與蛋白質合成的作用,代表轉錄因子NF-kB參與不飽和脂肪酸刺激視網膜色素細胞促進COX-2與iNOS表現的作用。我們進ㄧ歩探討不飽和脂肪酸促進活化NF-kB活化的機制,從RT-PCR分析,我們發現抗氧化劑--維他命E有效抑制不飽和脂肪酸刺激視網膜色素細胞促進COX-2與iNOS mRNA表現的作用。從NF-kB promoter reporter 分析,我們發現抗氧化劑--維他命也有抑制不飽和脂肪酸刺激促進NF-kB所調控基因的轉錄作用。以上結果代表不飽和脂肪酸誘發NF-kB活化,促進COX-2與iNOS表現的作用與氧化刺激有關。我們進ㄧ歩探討葉黃素能否抑制亞麻油酸刺激視網膜色素細胞促進COX-2與iNOS表現的作用。從RT-PCR與Western blot分析,我們發現葉黃素有效抑制亞麻油酸刺激視網膜色素細胞促進COX-2與iNOS mRNA表現與蛋白質合成的作用,並隨治療之葉黃素濃度的增加,抑制作用也隨之增加。從EMSA分析,我們發現葉黃素有效抑制亞麻油酸刺激促進NF-kB與NF-kB結合位置的結合能力。從NF-kB promoter reporter 分析,我們發現葉黃素也能抑制亞麻油酸刺激增加NF-kB所調控基因的轉錄作用。以上結果代表葉黃素具有抑制亞麻油酸所誘發NF-B活化與促進細胞表現COX-2與iNOS的作用。綜觀上述的結果,我們發現不飽和脂肪酸會刺激視網膜色素細胞,經由活化轉錄因子NF-kB而促進iNOS與COX-2 mRNA的表現與蛋白質的合成,並增加PGE2與NO的合成。在受試的脂肪酸中,以含有兩個不飽合鍵的亞麻油酸活化NF-kB與促進COX-2與iNOS表現的能力最強;含有一個不飽合鍵的油酸與含有三個不飽合鍵的亞麻油酸活化NF-kB與促進COX-2與iNOS表現的能力相當;飽和脂肪酸硬脂酸則無法活化NF-kB與促進COX-2與iNOS的表現。葉黃素能經由抑制亞麻油酸活化NF-kB的作用,進而抑制亞麻油酸促進COX-2與iNOS表現的作用。我們提出另ㄧ個葉黃素治療老年性黃斑部病變脈絡膜新生血管的分子機轉。本研究以分子生物的觀點支持之前流行病學的概念,就是減少亞麻油酸在飲食中的攝取,並多補充葉黃素有助於預防老年性黃斑部病變。
本論文第二部分主要是探討視網膜色素細胞移植來治療老年性黃斑部病變時,integrin的表現對視網膜色素細胞移植的影響。網膜下手術(submacular surgery)來移除黃斑部脈絡膜新生血管,是目前唯一能治癒老年性黃斑部病變脈絡膜新生血管的方式。然而目前的臨床研究資料顯示,接受手術切除脈絡膜新生血管的病患,由於手術過程中會破壞視網膜色素細胞,導致脈絡膜與視網膜神經在術後仍持續退化。因此在手術切除脈絡膜新生血管同時合併施行視網膜色素細胞移植,期望移植入的視網膜色素細胞能貼附在病患的Bruch’s membrane上,形成單一層的構造,以避免脈絡膜與視網膜神經的仍持續退化。然而,臨床資料顯示病患在合併接受視網膜色素細胞移植手術之後,病理組織檢查顯示移植入的視網膜色素細胞並沒有貼附在Bruch’s membrane上,形成單一層的構造。所以思考如何增加移植的視網膜色素細胞與Bruch’s membrane的貼附率,成為急待克服的問題,也是對以視網膜下手術來治療老年性黃斑部病變成功與否的一個非常重要的關鍵。
視網膜色素細胞要貼附在Bruch’s membrane上必須要靠視網膜色素細胞上的附著因子與細胞外間質(extracellular matrix),如:laminin,fibronectin,vitronectin.之間產生交互作用。Integrin α6、β4次單位所構成的integrinα6β4是laminin的受體,也是構成hemidesmosome的重要成份。Integrinα6β4普遍分布在上皮細胞的表面,是上皮細胞能與其下的細胞基底膜(basement membrane)形成緊密結合的重要成份之一。Laminin也是構成細胞基底膜的重要成份。因此本研究第二部分,我們首先探討人類視網膜色素細胞株,ARPE-19細胞,能否表現integrin α6與β4次單位。利用RT-PCR分析,我們發現ARPE-19細胞會表現integrin α6及β4mRNA。從流式細胞儀分析,我們發現ARPE-19細胞表面也會表現integrin α6及β4蛋白質。我們接著探討integrinα6β4次單位在ARPE-19細胞的功能。利用定點突變法(site-directed mutagenesis),在integrin α6與β4次單位的結合區(binding domain)產生定點突變,再將含有integrinα6與β4次單位突變cDNA的質體分別轉殖入ARPE-19細胞,利用細胞貼附試驗來分析細胞在 laminin 上之貼附率。我們發現ARPE-19細胞在轉殖入含integrin α6與β4次單位突變cDNA的質體後,細胞表面integrinα6與β4次單位的表現會減少,同時在laminin上的貼附率也減少,這代表integrinα6與β4次單位參與ARPE-19細胞貼附laminin的作用。接著我們進一步探討增加(overexpression)ARPE-19細胞上integrin α6與β4次單位的表現,能否增加ARPE-19在Bruch’s membrane上的貼附率。Bruch’s membrane的結構分為五層:視網膜色素細胞基底層(basal lamina layer)、內膠原質層(inner collagenous layer)、彈性纖維層(elastin layer)、外膠原質層(outer collagenous layer)、脈絡膜微血管基底層(basal lamina of choriocapilalris)。通常視網膜色素細胞移植是緊接在移除視網膜下新生血管膜之後,在移除視網膜下新生血管膜的過程中會傷害到Bruch’s membrane,所以被移植的細胞必須貼附在較深層的Bruch’s membrane。許多研究顯示越深層的Bruch’s membrane由於細胞外間質的含量較低,所以視網膜色素細胞的貼附率也越低。我們採用"Bruch’s membrane explant"的模式來探討ARPE-19細胞在Bruch’s membrane各個分層的貼附率,以模擬術中可能造成Bruch’s membrane不同的傷害程度。這是一種"ex vivo"的模式--由豬眼中取下Bruch’s membraneu,在體外利用物理與酵素的方式將Bruch’s membrnae一層一層逐一分離,如此可得到含有不同Bruch’s membrane分層的Bruch’s membrane explant。我們發現ARPE-19細胞在轉殖入integrinα6cDNA後,會增加細胞表面integrinα6,β4與β1次單位的表現。這些細胞在Bruch’s membrane的basal lamina層,inner collagenous層,elastic層與 outer collagenous層上的貼附率(adhesion rate)與增生率(proliferation rate),比mock轉殖或沒有轉殖的細胞,在統計學上有顯著的增加。而轉殖入integrinβ4cDNA的ARPE-19細胞只有在Bruch’s membrane的basal lamina層和inner collagenous層上的貼附率與增生率,比mock轉殖或沒有轉殖的細胞,在統計學上有顯著的增加。利用掃描式電子顯微鏡(scanning electronic microscope),我們進一步比較這些細胞在Bruch’s membrane的各層中,經過7天的培養之後,細胞的型態(morphology)與增生覆蓋(coverage)的情形。我們發現ARPE-19細胞在轉殖入α6cDNA後可增生並幾乎完全覆蓋Bruch’s membrane的basal lamina層,inner collagenous層,elastic層與outer collagenous層。轉殖入α6cDNA的ARPE-19細胞在basal lamina層上呈現扁平、均勻六角形形狀,並互相接觸形成連續的一層構造。在inner collagenous層,轉殖入α6cDNA的ARPE-19細胞依然呈現扁平的形狀,並形成連續的一層,然而有些地方會出現細胞間的縫隙(gap)。在elastic層,轉殖入α6cDNA的ARPE-19細胞,細胞的形狀比較不規則,細胞間的縫隙更多,在某些縫隙的邊緣,細胞會朝向縫隙的方向伸出偽足(pseudopodia)。在outer collagenous層,雖然細胞大致上能夠增生並覆蓋整個explant,然而在explant上仍然會出現許多沒有視網膜色素細胞覆蓋的細胞缺陷(defects),在缺陷的邊緣,有些細胞依然呈現圓形的型態,並沒有呈現扁平。而轉殖入β4cDNA的ARPE-19細胞,幾乎可覆蓋Bruch’s membrane的basal lamina層和 inner collagenous層。在basal lamina層,轉殖入β4cDNA的ARPE-19細胞與轉殖入α6cDNA的細胞ㄧ樣,也會呈現均勻六角形形狀,並形成連續的一層。在inner collagenous 層,細胞大致上能夠增生而覆蓋整個explant,但也會出現一些缺陷與縫隙。然而,轉殖入β4cDNA的ARPE-19細胞並無法貼附與存活在Bruch’s membrane的elastic層與outer collagenous 層。因此,經過7天的培養,在電子顯微鏡下,所有細胞都已死亡,只留下細胞碎片。至於控制組的mock轉殖細胞只能覆蓋Bruch’s membrane的basal lamina層。這些結果顯示,人類視網膜色素細胞株ARPE-19細胞表面會表現integrin α6β4,並藉由integrinα6β4,使細胞能貼附在laminin上。將ARPE-19細胞先在體外轉殖入α6cDNA,可增加細胞表面integrinα6、β4與β1的表現,並可增加細胞在Bruch’s membrane explant 上所有層的貼附率、增生率與覆蓋率。因此,我們認為增加細胞表面integrin的表現,是增加視網膜色素細胞移植手術成功機率一個重要的策略。本研究也提供另一個以ex vivo基因轉殖的方式,來增加移植細胞的貼附率,已期提高以脈絡膜切除來治療老年性黃斑部病變的成功率。
黃斑部下出血是老年性黃斑部病變脈絡膜新生血管的合併症之一。長期未吸收的黃斑部下出血會對黃斑部視網膜產生永久的傷害,嚴重影響病患的視力預後。組織胞漿素原活化劑是一種絲胺酸蛋白酶(serine proteinase),可以將胞漿素原(plasminogen) 活化變成胞漿(plasmin),而能將血塊中的纖維蛋白(fibrin)溶解形成可溶解性分解產物(soluble degradation products)。許多小規模的臨床研究顯示玻璃體注射組織胞漿素原活化劑(tPA)當輔劑,合併氣體移位法(pneumatic displacement)來治療黃斑部下出血的效果相當不錯。然而玻璃體內注射組織胞漿素原活化劑也有一些潛在的副作用,包括:組織胞漿素原活化劑本身所具有的視網膜毒性、玻璃體注射過程中可能會造成眼內炎、視網膜剝離或裂孔的併發症。更重要的是有文獻報告某些病患只要單獨玻璃體內注射長效性氣體,不用注射組織胞漿素原活化劑也同樣能有效地將血塊移位,因此他們認為玻璃體內注射組織胞漿素原活化劑當輔劑是不必要,反而具有潛在的危險性。而動物實驗關於玻璃體內注射組織胞漿素原活化劑,是否能穿透視網膜,並在視網膜下產生治療效果,尚未得到ㄧ致的結論。因此本論文第三部分主要是探討臨床上利用組織胞漿素原活化劑(t-PA)當輔助劑,來協助長效型氣體位移老年性黃斑部病變黃斑下出血的效果。我們回溯性比較因老年性黃斑部病變產生黃斑部下出血的病患,在接受玻璃體注射組織胞漿素原活化劑合併氣體移位法或只有單獨注射長效性氣體後,視力結果(visual outcomes)、解剖結果(anatomic outcomes)與治療過程的副作用。其中,視力結果包括:術後最佳矯正視力(best postoperative visual acuity)、最終視力(final visual acuity)進步的比率;解剖結果(anatomic outcomes)包括:血塊被完全位移(complete displacement)的比率;副作用包括:眼壓升高、玻璃體出血、網膜毒性與眼內炎的比率。同時我們根據出血的時間長短將病患分為兩個次族群(subgroup),來探討出血的時間長短是否會影響玻璃體注射組織胞漿素原活化劑的治療效果。我們也利用多變量羅吉斯回歸分析(multiple logistic regression analysis)來探討影響氣體移位術來治療老年性黃斑部病變黃斑部下出血之病患術後最佳矯正視力的因子。
我們收集從1998年1月到2003年10月所有在臺大醫院眼科門診被診斷為老年性黃斑部病變並合併有黃斑部下出血,並接受氣體位移治療的病患。將其病歷做詳盡的紀錄與分析。我們將病患分為兩組: ㄧ組只接受玻璃體內注射長效型氣體,包括: perfluoro-propane (C3F8)或 perfluoro- propane (SF6)( "只有長效型氣體"治療組)。另一組則接受玻璃體內注射組織胞漿素原活化劑合併玻璃體注射長效型氣體("組織胞漿素原活化劑與長效型氣體"治療組)。所有病患都至少追蹤超過6個月以上。研究結果發現,"組織胞漿素原活化劑與長效型氣體"治療組在達到"進步"(視力增加兩行或兩行以上)的術後最佳矯正視力與血塊"完全位移"的比率比"只有長效型氣體"治療組高,並達到統計學上顯著的差異。然而,經由次族群分析(subgroup analysis),我們發現"在出血期間小於14天"的病患次族群,"組織胞漿素原活化劑與長效型氣體"治療組與"只有長效型氣體"治療組在達到"進步"的術後最佳矯正與血塊"完全位移"的比率,並達到統計學上顯著的差異。只有在"出血的時間大於14 天"的病患次族群中,"組織胞漿素原活化劑與長效型氣體"治療組在術後達到"進步"的術後最佳視力的比率比"只有長效型氣體"治療組大,並達到統計學上顯著的差異。這結果代表組織胞漿素原活化劑在協助氣體位移黃班部下出血,只有在出血期間相對比較久的病患,才能顯現出效果。然而,無論是在"出血期間大於"或"小於14天"的病患次族群中,病患的最終視力在兩治療組之間都沒有統計學上顯著的差異。而"組織胞漿素原活化劑與長效型氣體"治療組與"只有長效型氣體"治療組在手術過程的副作用包括:眼壓升高、玻璃體出血、網膜毒性與眼內炎的比率,都沒有達到統計學上顯著的差異。以上結果顯示,對於出血期間相對比較久的病患,玻璃體內注射組織胞漿素原活化劑來輔助治療黃班部下出血,能夠使其將血塊完全位移,很快恢復術後最佳視力,但並無法改變其視力的預後。利用多變項羅吉斯回歸分析,我們發現"早接受治療" (在本研究是定義出血小於等於14 天)的病患,在治療後達到"進步"術後最佳矯正視力的比率比"晚接受治療" (定義為出血期間大於14天)的病患高,並達到統計學上顯著的差異。至於是否使用組織胞漿素原活化劑當做輔劑(adjuvant),對於能否在治療後達到"進步"的術後最佳矯正視力,只有達到統計學上邊緣的差異(borderline significance),這代表早期接受治療是影響氣體位移黃斑部下出血治療效果最重要的因子。經由以上研究,我們得到以下結論:老年性黃斑部病變病患出現黃斑部下出血時,早期接受氣體位移治療有助於血塊的位移,已得到較好的術後最佳矯正視力。玻璃體內注射組織胞漿素原活化劑來協助氣體位移黃班部下出血,只有在出血期間相對比較久的病患,才具有治療效果。基於以上的結論,我們提出一個對於老年性黃斑部病變病患出現黃斑部下出血的治療範本(protocol):對於剛發生黃斑部下出血的老年性黃斑部病變患者我們建議採用分階段治療(staged procedure):病患先儘快接受玻璃體注射氣體的治療,如果病患在俯臥48-72小時後依然沒有產生明顯足夠的位移作用時,才考慮玻璃體內再注射組織胞漿素原活化劑來協助血塊的位移。對於出血期間較久的病患,則ㄧ開始就直接接受玻璃體內注射組織胞漿素原活化劑與長效性氣體的治療。
口試委員、指導教授與所長簽名表 I
國家圖書館碩博士論文授權書 II
致謝 III
目錄 V
縮寫對照表 VIII
圖表目錄 X
中文摘要 1
ㄧ、緒論
1.1 老年性黃斑部病變在臨床上的重要性 10
1.2 老年性黃斑部病變臨床上的表現 10
1.3 老年性黃斑部病變的病理變化及可能的致病機轉 11
1.3.1 一氧化氮聚合酶(NOS)與老年性黃斑部病變的關聯 13
1.3.2 前列腺素合成酵素(COX)與老年性黃斑部病變的關聯 14
1.4 老年性黃斑部病變的危險因子 14
1.4.1 脂肪酸與老年性黃斑部病變的關聯 15
1.4.2 脂肪酸、亞麻油酸與細胞基因的調節 16
1.4.3 NF-kB的文獻回顧 17
1.4.4 MAPK路徑的文獻回顧 18
1.5 老年性黃斑部病變脈絡膜新生血管治療方法的文獻回顧 19
1.5.1 葉黃素與老年性黃斑部病變 22
1.5.2 網膜下手術切除黃斑部脈絡膜新生血管的文獻回顧 23
1.5.2.1 臨床上視網膜色素細胞移植之結果 24
1.5.2.2 integrin的文獻回顧 24
1.5.2.3 視網膜色素細胞移植的文獻回顧 26
1.6 老年性黃斑部病變產生黃斑部下出血治療方法之文獻回顧 28
1.6.1 纖維蛋白溶解系統(fibrinolytic system)之文獻回顧 29
1.6.2玻璃體注射組織胞漿素原活化劑合併氣體移位法治療黃斑部下出血之文獻回顧 29
1.6.3 玻璃體注射組織胞漿素原活化劑合併氣體移位法治療黃斑部下出血之副作用 30
1.6.4玻璃體注射組織胞漿素原活化劑合併氣體移位法治療黃斑部下出血,目前尚未解決的問題 31
1.7 欲研究的問題及其重要性、研究的假說與特定目的
1.7.1.1老年性黃斑部病變脈絡膜新生血管之分子機轉--亞麻油酸刺激視網膜色素細胞產生促進發炎因子COX-2 與iNOS表現的相關研究 33
1.7.1.2 老年性黃斑部病變飲食預防之分子機轉—比較各種脂肪酸刺激視網膜色素細胞促進COX-2 與iNOS的表現與葉黃素治療機轉的相關研究 35
1.7.2 視網膜色素細胞上integrin的表現對視網膜色素細胞移植的影響 38
1.7.3 玻璃體注射組織胞漿素原活化劑當輔劑協助氣體位移治療老年性黃斑部病變病患產生的黃斑部下出血 41
二、方法
2.1.1 老年性黃斑部病變致病機轉--亞麻油酸與脂肪酸刺激視網膜色素細胞產生促進發炎因子COX-2與iNOS表現的相關研究 44
2.1.2老年性黃斑部病變飲食預防之分子機轉—比較各種脂肪酸刺激視網膜色素細胞促進COX-2 與iNOS的表現與葉黃素治療機轉的相關研究 44
2.2 視網膜色素細胞上integrin的表現對視網膜色素細胞移植的影響 51
2.3 玻璃體注射組織胞漿素原活化劑當輔劑協助氣體位移治療老年性黃斑部病變病患產生的黃斑部下出血 56
三、結果
3.1.1 老年性黃斑部病變致病機轉--亞麻油酸與脂肪酸刺激視網膜色素細胞產生促進發炎因子COX-2與iNOS表現的相關研究 59
3.1.2老年性黃斑部病變飲食預防之分子機轉—比較各種脂肪酸刺激視網膜色素細胞促進COX-2 與iNOS的表現與葉黃素治療機轉的相關研究 63
3.2 視網膜色素細胞上integrin的表現對視網膜色素細胞移植的影響 68
3.3 玻璃體注射組織胞漿素原活化劑當輔劑協助氣體位移治療老年性黃斑部病變病患產生的黃斑部下出血 72
四、討論
4.1.1老年性黃斑部病變致病機轉--亞麻油酸與脂肪酸刺激視網膜色素細胞產生促進發炎因子COX-2與iNOS表現的相關研究 76
4.1.2老年性黃斑部病變飲食預防之分子機轉—比較各種脂肪酸刺激視網膜色素細胞促進COX-2 與iNOS的表現與葉黃素治療機轉的相關研究 80
4.2 視網膜色素細胞上integrin的表現對視網膜色素細胞移植的影響 84
4.3 玻璃體注射組織胞漿素原活化劑當輔劑協助氣體位移治療老年性黃斑部病變病患產生的黃斑部下出血 90
五、展望
5.1.1.老年性黃斑部病變致病機轉--亞麻油酸與脂肪酸刺激視網膜色素細 胞產生促進發炎因子COX-2與iNOS表現的相關研究 95
5.1.2老年性黃斑部病變飲食預防之分子機轉—比較各種脂肪酸刺激視網膜色素細胞促進COX-2 與iNOS的表現與葉黃素治療機轉的相關研究 98
5.2 視網膜色素細胞上integrin的表現對視網膜色素細胞移植的影響 100
5.3 玻璃體注射組織胞漿素原活化劑當輔劑協助氣體位移治療老年性黃斑部病變病患產生的黃斑部下出血 103
六、論文英文簡述 105
七、參考文獻 113
八、圖表 135
九、附錄:個人在博士班修業期間所發表之相關論文 171
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