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        視網(wǎng)膜缺血再灌注損傷的藥物治療進(jìn)展

        2013-12-31 00:00:00路璐王林洪鄧淑娟
        中國醫(yī)學(xué)創(chuàng)新 2013年24期

        【關(guān)鍵詞】 視網(wǎng)膜; 缺血再灌注; 進(jìn)展

        缺血的組織器官在恢復(fù)血液灌注后,部分組織器官的原有功能并沒得到改善,并且結(jié)構(gòu)破壞的更加嚴(yán)重,甚至出現(xiàn)不可逆的損傷,稱為缺血再灌注損傷[1]。對于缺血再灌注損傷造成的心臟和大腦的研究開展的較早,取得了一定的成就。視網(wǎng)膜作為大腦的延伸部分,結(jié)構(gòu)精細(xì)復(fù)雜,新陳代謝旺盛,對缺血更敏感。缺血再灌注后可以引發(fā)多種眼科疾病,引起了眼科醫(yī)生的廣泛關(guān)注[2]。本文參考國內(nèi)外文獻(xiàn),將目前視網(wǎng)膜缺血再灌注(retinal ischemia reperfusion,RIR)損傷的藥物治療情況做一綜述,并期待對臨床工作提供有益的參考。

        1 拮抗氧自由基及氧化應(yīng)激

        自由基作為一個(gè)靶點(diǎn),觸發(fā)后可以引起一系列的鏈?zhǔn)椒磻?yīng),通過不同通路對細(xì)胞自身及視網(wǎng)膜組織帶來嚴(yán)重?fù)p害[3]。蛋白質(zhì)、DNA及脂質(zhì)都可與自由基一起發(fā)生氧化反應(yīng),帶來細(xì)胞結(jié)構(gòu)和功能的破壞。自由基主要損害細(xì)胞膜的完整性,造成細(xì)胞膜屏障功能的喪失[4]。同時(shí)也可以改變NA+-K+-ATP泵的功能和部分細(xì)胞膜酶的活性。線粒體膜受到損害后[5],ATP無法進(jìn)入氧化磷酸化從而引起細(xì)胞能量供應(yīng)障礙。在細(xì)胞結(jié)構(gòu)上引起嚴(yán)重?fù)p害。線粒體中的多聚核糖核蛋白脫落[6],蛋白質(zhì)合成受到抑制。溶酶體膜受損后,釋放出多種組織水解酶,進(jìn)行自身溶解,嚴(yán)重者以致引起細(xì)胞破裂凋亡。DNA與自由基發(fā)生氧化反應(yīng)后可直接導(dǎo)致細(xì)胞死亡或凋亡[7]。通過各種手段阻止氧自由基與氧化應(yīng)激反應(yīng)的發(fā)生發(fā)展,成為治療RIR損傷的一個(gè)重要途徑。

        目前研究已經(jīng)明確,雌激素在體內(nèi)通過結(jié)構(gòu)活性轉(zhuǎn)化來對抗氧化作用[8]。谷胱甘肽過氧化物酶(glutathione peroxidase,GPx)、超氧化物歧化酶、谷氨酰半胱氨酸連接酶(glutamate-cysteine ligase,GCLc)、二氧化錳歧化酶、過氧化氫酶(catalase,CAT)都能有效的抑制RIR引發(fā)的氧化應(yīng)激反應(yīng)[9]。隨著中醫(yī)藥技術(shù)的全面普及,國內(nèi)外學(xué)者對中藥進(jìn)一步提取?,F(xiàn)在,如葛根、丹參、姜黃、牛磺酸、補(bǔ)陽還五湯、拳參和生姜等提取物、β-七葉皂苷鈉、天麻等[10]通過實(shí)驗(yàn)證實(shí)具有改善視網(wǎng)膜厚度,穩(wěn)定視網(wǎng)膜神經(jīng)節(jié)細(xì)胞的作用可以不同程度改善和抑制缺血再灌注后的氧化損傷。

        2 拮抗一氧化氮的作用

        RIR的時(shí)候,視網(wǎng)膜內(nèi)核層的無長途細(xì)胞激活一氧化氮合酶(nitricoxide synthase,NOS) [11]。NOS分為三種不同的亞型內(nèi)皮細(xì)胞型(eNOS)、神經(jīng)型(nNOS)、誘導(dǎo)型(iNOS)。其中以eNOS表達(dá)較多。分子氧與受到eNOS催化L-精氨酸反應(yīng)生成高濃度的NO,一氧化氮與氧氣反應(yīng)生成過氧亞硝酸離子(ONOO-)。ONOO-化學(xué)性質(zhì)很活躍,質(zhì)子化生成過氧亞硝酸(ONOOH)然后分解產(chǎn)生OH和NO[12]。精氨酸可以抑制一氧化氮合酶的活性,抑制NO的產(chǎn)生[13]。氨基胍作為一氧化氮合酶的高選擇性抑制劑,通過抑制iNOS的合成阻斷化學(xué)反應(yīng)的進(jìn)行,更加高效的阻止NO生成[14]。它延緩了由于缺血導(dǎo)致的視網(wǎng)膜變性損傷,效果較精氨酸強(qiáng)7倍。沒食子酸作用于NOS產(chǎn)生環(huán)節(jié),對視網(wǎng)膜神經(jīng)節(jié)細(xì)胞產(chǎn)生保護(hù)作用?;前樊悙哼蜃鳛閮?nèi)皮素受體的抑制劑,可以減少nNOS的生成,使視網(wǎng)膜電流圖的a波b波恢復(fù)[15]。

        3 抑制鈣離子超載

        鈣離子超載在RIR損傷中有著重要的作用,并作為一種共同的損傷途徑廣泛地參與其他破壞機(jī)制[16]。視網(wǎng)膜缺血時(shí),過量的鈣離子激活NMDA受體通道,造成電壓門控性鈣離子通道開放Na+-Ca2+交換異常進(jìn)行等途徑,繼而引發(fā)細(xì)胞內(nèi)的鈣離子游離出儲存庫向胞漿內(nèi)釋放[17]。線粒體的功能障礙,無法生成足夠的ATP進(jìn)行細(xì)胞生理活動(dòng)鈣泵功能首先受到影響無法正常運(yùn)行[18]。游離的鈣離子無法及時(shí)的排出和再攝取,導(dǎo)致細(xì)胞內(nèi)游離的鈣離子增加、引起細(xì)胞內(nèi)鈣離子級聯(lián)反應(yīng)。一系列的酶異常激活、大量自由基產(chǎn)生、血小板聚集、細(xì)胞膜降解。嚴(yán)重時(shí)可導(dǎo)致細(xì)胞的變性壞死或激活細(xì)胞的凋亡進(jìn)程。在動(dòng)物缺血再灌注模型中,NS-7作為Na+-Ca2+通道阻滯劑可以阻滯b波振幅,保護(hù)神經(jīng)[19]。雌激素通過改變靜息電位,抑制細(xì)胞外鈣離子的流入和自身細(xì)胞內(nèi)儲存鈣的釋放,減輕鈣超載引發(fā)的遲發(fā)型神經(jīng)元細(xì)胞壞死。另外各種鈣通道阻滯劑如美托洛爾和鈣蛋白酶抑制劑等都可以減少細(xì)胞內(nèi)鈣離子的升高,拮抗NMDAhang的視網(wǎng)膜毒性,減輕RIR的鈣離子超載引起的損害[20]。

        4 干預(yù)白細(xì)胞作用及炎癥反應(yīng)

        再灌注損傷時(shí),各種炎癥細(xì)胞因子最早出現(xiàn)[21],并逐漸增多引起白細(xì)胞聚集,白細(xì)胞在各種細(xì)胞因子的趨化作用下大量進(jìn)入了視網(wǎng)膜組織。白細(xì)胞在聚集過程中自身也產(chǎn)生大量的炎癥介質(zhì),正反饋的造成微循環(huán)中的白細(xì)胞數(shù)量劇增[22]。缺血再灌注的早期,白細(xì)胞粘附于內(nèi)皮細(xì)胞處,形成無復(fù)流現(xiàn)象,阻礙了有效的微循環(huán)[23]。產(chǎn)生的各種氧自由基,激發(fā)細(xì)胞膜的脂質(zhì)過氧化,在缺血再灌注損傷區(qū),白細(xì)胞釋放出酶性顆粒,導(dǎo)致視網(wǎng)膜受到進(jìn)一步損害。目前動(dòng)物實(shí)驗(yàn)表明,缺血后產(chǎn)生的大量氧自由基被β-七葉皂苷鈉中和,阻止了IL-6的表達(dá),對視網(wǎng)膜起到保護(hù)作用[24]。從銀杏葉中提取的黃酮和銀杏內(nèi)酯,具有清除自由基抑制血小板活化因子,促進(jìn)血液循環(huán)改善阻止缺氧和細(xì)胞水腫抗氧化等作用[25]。下調(diào)ICAM-1表達(dá),減輕炎癥因子的損傷。阿片受體激動(dòng)劑可以抑制TNF-α的產(chǎn)生,減少早期RIR的損傷[26]。人血紅素合酶抑制NF-kb表達(dá),也可以起到保護(hù)視網(wǎng)膜的作用[27]。

        5 炎性基因調(diào)控

        AQP-4在視網(wǎng)膜muller細(xì)胞中表達(dá)[28]。K離子通道功能主要依靠Muller細(xì)胞和AQP-4的調(diào)節(jié)。在RIR損傷的老鼠模型中發(fā)現(xiàn),AQP-4基因缺失的老鼠視網(wǎng)膜細(xì)胞和功能都有明顯的改善[29]。CDDD-Me作為反轉(zhuǎn)錄因子Nrf2的激活劑在動(dòng)物實(shí)驗(yàn)中可以明顯的增加抗氧化劑相關(guān)基因的表達(dá),在RIR損傷中起到保護(hù)細(xì)胞的作用[30]。另外,在RIR模型中注射脂質(zhì)體ATP能明顯降低神經(jīng)節(jié)細(xì)胞層中細(xì)胞的死亡,通過降低前炎性基因表達(dá),減少了白介素1β(IL-1β)、細(xì)胞間粘附分子1(ICAM-1)、一氧化氮合酶2(NOS-2)、趨化因子配體2、5、10、白介素6(IL-6)及腫瘤壞死因子(TNF)等的產(chǎn)生[31-32]。

        6 阻止細(xì)胞凋亡

        早期實(shí)驗(yàn)研究發(fā)現(xiàn)在RIR模型中視網(wǎng)膜神經(jīng)節(jié)細(xì)胞層和內(nèi)核層存在著凋亡細(xì)胞[33]。最近的研究進(jìn)一步明確了缺血再灌注損傷與細(xì)胞凋亡有著密切的關(guān)系[34]。RIR后立刻將色素上皮原性因子注入玻璃體腔,可以觀察到視網(wǎng)膜神經(jīng)節(jié)細(xì)胞的損害得到明顯的減弱[35]。中藥川弓嗪可以阻斷缺血再灌注動(dòng)物模型的視網(wǎng)膜細(xì)胞DNA凋亡樣斷裂。雌激素上調(diào)bcl-2mRNA的表達(dá),促紅細(xì)胞生成素抑制caspase-3基因蛋白表達(dá)等不同途徑起到抑制細(xì)胞凋亡的作用[36]。吸入一氧化碳在抑制caspase-3、TNF-α表達(dá)的同時(shí)還可以增強(qiáng)HSP-70蛋白的表達(dá)。保護(hù)了缺血再灌注中損傷的神經(jīng)節(jié)細(xì)胞[37-38]。

        總之,RIR損傷是一系列的損傷機(jī)制共同作用的結(jié)果。各種機(jī)制的具體通路和作用方式目前還不是非常清楚,通過大量的基礎(chǔ)實(shí)驗(yàn)對各種機(jī)制的進(jìn)一步深入研究,取得突破,定會給藥物研制指引新的方向,對臨床上RIR疾病的治療帶來很大的幫助。

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        (收稿日期:2013-03-18) (本文編輯:歐麗)

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