藥物溶栓和機械取栓是缺血性卒中的最有效治療方法，伴隨其日益普及，缺血再灌注損傷成為很多缺血性卒中患者和臨床醫(yī)師要面臨的挑戰(zhàn)。加利福尼亞大學(xué)的Atsushi Mizuma等綜述神經(jīng)系統(tǒng)缺血再灌注損傷的基礎(chǔ)和臨床進展，發(fā)表于2018年7月的Stroke雜志，全文翻譯如下。

用r-tPA（recombinant tissue-type plasminogen activator）進行藥物血管再通已成為急性缺血性腦卒中（IS）的主要治療手段¹。近期隨機對照試驗進一步證實機械取栓（MT）的價值^2-4。雖然急性期治療的主要目標(biāo)是恢復(fù)血流，而如果再通太遲，與未恢復(fù)血流相比其損傷會更大⁵。這主要是由于產(chǎn)生過量的活性氧類（ROS），其可直接或通過觸發(fā)炎癥反應(yīng)而間接損傷神經(jīng)細胞。炎癥導(dǎo)致產(chǎn)生損傷性免疫介質(zhì)、效應(yīng)分子和更多的ROS⁶。ROS也可通過DNA/RNA損傷和脂質(zhì)過氧化引起細胞凋亡/壞死。這一循環(huán)稱為再灌注損傷（R/I；見圖）。

筆者將聚焦R/I的潛在機制和針對實驗性血管再通模型中這些機制的實驗室研究（如tMCAO或血栓栓塞性卒中）（表1）^10-18。同時我們也會綜述一下過去和現(xiàn)今的相關(guān)臨床試驗，有些與血管再通聯(lián)合應(yīng)用（表2）^19-30。

卒中后炎癥反應(yīng)被認為會加重缺血損傷?？蓪?dǎo)致惡化的免疫分子包括炎癥細胞因子、化學(xué)因子和免疫細胞產(chǎn)生的活性成分。腦細胞缺血損傷后，免疫細胞激活首先發(fā)生于小膠質(zhì)細胞并釋放免疫分子。隨后，白細胞激活并浸潤腦組織。一些實驗室研究顯示，阻止白細胞浸潤可改善卒中模型的結(jié)局，雖然其臨床效果尚未被證實³¹。

卒中后即出現(xiàn)炎癥反應(yīng)，因缺血性腦細胞會導(dǎo)致分泌一系列分子，這些分子統(tǒng)稱為損傷相關(guān)分子模式。這些分子包括高遷移率簇蛋白B，過氧化物酶，嘌呤類，核苷酸類（包括ATP和UDP）和核酸片段^6,31。損傷相關(guān)分子模式結(jié)合小膠質(zhì)細胞和白細胞上的固有免疫受體（如Toll樣和嘌呤受體），使其激活，然后激活炎性轉(zhuǎn)錄因子（核因子-κB和絲裂原活化蛋白激酶）。這些因子缺乏或藥物將其阻斷可顯著保護卒中的實驗動物^32,33。這些因子可促進細胞因子，化學(xué)因子，黏附分子，基質(zhì)金屬蛋白-9（MMP-9），誘導(dǎo)型一氧化氮合酶和NADPH氧化酶（NOX）的產(chǎn)生，加重缺血損傷。促炎細胞因子白細胞介素（IL）-1β的影響可遠及細胞翻譯層面。

在一項II期臨床試驗，人類重組IL-1受體拮抗劑（IL-1β的內(nèi)源性抑制劑）減少了梗塞體積并改善3個月的神經(jīng)系統(tǒng)結(jié)局³⁴。T細胞釋放的促炎細胞因子（干擾素γ，IL-17,和IL-23）近期正作為治療靶標(biāo)研究。IL-17促進腫瘤壞死因子-α（TNF-α），IL-1β和MMP-9的表達，而IL-23則誘導(dǎo)IL-17的表達³⁵。抑制這些細胞因子可改善實驗R/I模型的神經(jīng)系統(tǒng)結(jié)局。

在tMCAO后，小膠質(zhì)細胞/巨噬細胞表達TNF-α誘導(dǎo)型蛋白8-樣分子2，可起到抗炎作用。而TNF-α誘導(dǎo)型蛋白8-樣分子2缺失型小鼠在tMCAO后則加重神經(jīng)系統(tǒng)結(jié)局和炎癥反應(yīng)³⁶。IL-10，IL-4和轉(zhuǎn)化生長因子-β1是抗炎細胞因子，在卒中模型中均似與神經(jīng)系統(tǒng)結(jié)局改善相關(guān)^6,37。MMP-9由免疫細胞表達，可通過破壞血腦屏障（BBB）促進炎癥反應(yīng)。另外，內(nèi)源性tPA激活纖溶酶，并進一步激活MMP-9。因此，應(yīng)用r-tPA可能促進出血，如果入腦還可導(dǎo)致腦水腫，而MMP-9則成為一個相關(guān)治療靶標(biāo)³⁸。

一些抗炎療法已經(jīng)在卒中模型中應(yīng)用，尤其是與r-tPA聯(lián)用。米諾環(huán)素具有多重抗細胞死亡效應(yīng)，可改善神經(jīng)系統(tǒng)結(jié)局并降低r-tPA相關(guān)的HTf¹⁰。米諾環(huán)素保護作用的一個機制可能是其通過阻斷P38絲裂原活化蛋白激酶抑制小膠質(zhì)細胞激活的能力。米諾環(huán)素也能通過抑制MMP改善BBB的完整性³⁹。BB-94是一個MMP-9抑制劑，可降低兔卒中模型中r-tPA誘導(dǎo)的HTf¹¹。然而，MMPs參與神經(jīng)血管重塑，長期抑制可能阻礙修復(fù)作用⁴⁰。表沒食子兒茶素沒食子酸酯（在綠茶中發(fā)現(xiàn)）因其抗氧化和神經(jīng)保護特性而受到關(guān)注。

在卒中模型，表沒食子兒茶素沒食子酸酯下調(diào)MMP-2和MMP-9，同時上調(diào)纖溶酶原激活物抑制劑-1¹²。沒食子兒茶素沒食子酸酯與r-tPA聯(lián)用可延長r-tPA的治療時間窗并減少腦水腫和BBB破壞¹²。顆粒蛋白前體（腦內(nèi)的一種生長因子）被認為有抗炎和血管保護作用，缺血性卒中后其在小膠質(zhì)細胞和內(nèi)皮細胞中顯著增加¹³。r-tPA聯(lián)合顆粒蛋白前體在卒中模型中顯示出改善神經(jīng)系統(tǒng)結(jié)局和減少腦出血與腦水腫的作用。粒細胞集落刺激因子可能通過抗炎作用而提供神經(jīng)保護41。在一個tMCAO模型中，相較于單獨應(yīng)用r-tPA，聯(lián)用粒細胞集落刺激因子可減少HTf并改善神經(jīng)系統(tǒng)結(jié)局¹⁴。

IS后的再灌注通過線粒體呼吸鏈和NOX誘發(fā)氧化應(yīng)激。缺血的線粒體被再灌注后產(chǎn)生的ROS充填，但不能有效地將其中和。內(nèi)源性抗氧化酶（超氧化物歧化酶、谷胱甘肽過氧化物酶和過氧化氫酶）的過表達已證實可改善實驗性卒中的結(jié)局。過表達超氧化物歧化酶的轉(zhuǎn)基因小鼠可顯著減少實驗tMCAO模型的卒中面積，而超氧化物歧化酶缺失型小鼠結(jié)局較差⁴²。過表達其它內(nèi)源性抗氧化劑，如谷胱甘肽過氧化物酶和過氧化氫酶，也有類似的神經(jīng)保護作用⁴³。在臨床層面，依布硒啉（ebselen，一種谷胱甘肽過氧化物酶類似物）可改善起病6小時內(nèi)IS患者的神經(jīng)系統(tǒng)結(jié)局⁴⁴。

免疫細胞通過NOX途徑產(chǎn)生超氧化物，可加劇氧化應(yīng)激⁴⁵。抑制NOX顯示可改善實驗性卒中的結(jié)局⁴⁵。但NOX也可能在高血糖誘導(dǎo)的卒中惡化中扮演重要角色。葡萄糖可通過磷酸己糖支路代謝，產(chǎn)生NADPH，為生成NOX提供底物。羅布麻寧是一種NOX抑制劑，可改善實驗中高血糖性tMCAO的結(jié)局⁴⁶，減少高血糖誘發(fā)性BBB破壞的惡化及r-tPA應(yīng)用時的HTf⁴⁷。

在過去這些年，還研究過其它相關(guān)治療策略。自由基清除劑（如替拉扎特或NXY-059聯(lián)合r-tPA）在實驗性卒中均有效果¹⁵，但在臨床研究中是陰性的^48,49。PSD-95蛋白（postsynaptic density-95，突觸后致密物-95）與N-甲基-D-門冬氨酸受體相關(guān)。其募集神經(jīng)源性一氧化氮合成酶，從而產(chǎn)生神經(jīng)毒性一氧化氮⁵⁰。PSD-95抑制劑NA-1可改善實驗性R/I的結(jié)局。胰島素樣生長因子是一種參與促存活信號通路的多效能肽，也可抑制氧化與氮化應(yīng)激⁵¹。尿酸通過抗氧化作用改善血栓栓塞卒中模型的結(jié)局¹⁶。依達拉奉是ROS清除劑，與r-tPA聯(lián)用也可改善實驗?zāi)Ｐ偷纳窠?jīng)系統(tǒng)結(jié)局¹⁷，在日本用于臨床急性IS的治療¹⁹。

ROS介導(dǎo)的損傷引起細胞凋亡，可能與R/I尤為相關(guān)。因為凋亡需要消耗細胞能量儲備以促進細胞死亡⁵²。線粒體發(fā)起的凋亡稱為內(nèi)源性途徑。此時，線粒體向胞漿釋放細胞色素C，與凋亡蛋白酶激活因子1和procaspase-9形成凋亡體⁵³。凋亡體激活caspase-9并激活效應(yīng)分子caspase-3，促進DNA清除⁵²。超氧化物歧化酶過表達小鼠在R/I時顯示出凋亡減少和細胞色素C移位，阻斷線粒體源性caspase激活劑和線粒體絲氨酸蛋白酶也能達到此效果⁵⁴。

Bcl-2家族參與凋亡的分子包括BAX、BAD和BID，它們觸發(fā)細胞色素C釋放，而Bcl-2和Bcl-XL阻礙其釋放⁵²。改變這些分子的平衡利于抗凋亡亞型的形成，可改善實驗卒中的結(jié)局。當(dāng)死亡受體與其受體結(jié)合，啟則動外源性凋亡途徑。研究廣泛的受體-配體組合是Fas/FasL。FasL與Fas結(jié)合，激活caspase-8，最終激活caspase-3并清除DNA⁵²。具有Fas突變的小鼠可少受R/I損害⁵⁵。

最后，雌激素已知參與IS。與雄性動物相比，雌性動物在實驗性卒中后結(jié)局更好。17-β雌二醇（E2）的保護作用可能與Bcl-2上調(diào)和抑制凋亡有關(guān)⁵⁶。因此，性別特異性類固醇可能與凋亡調(diào)節(jié)關(guān)聯(lián)。

雖然已經(jīng)在實驗卒中模型中研究了一些藥物與r-tPA聯(lián)用預(yù)防R/I，也有臨床研究進行聯(lián)用r-tPA和MT的探索。雖然沒有刻意針對預(yù)防R/I設(shè)計，這些研究可為未來相關(guān)研究提供框架。

依達拉奉聯(lián)合r-tPA/MT已經(jīng)在日本用于臨床。雖然缺乏對照組，2個觀察性研究具有提示作用。PROTECT4.5（Post-marketing Registry on Treatment With Edaravone in Acute Cerebral Infarction by the Time Window of 4.5 Hours）評價依達拉奉聯(lián)用r-tPA，提示這一組合可能增加較好結(jié)局的機會，減少HTf¹⁹。YAMATO（Tissue-Type Plasminogen Activator and Edaravone Combination Therapy）提示，應(yīng)用r-tPA后，良好結(jié)局與依達拉奉應(yīng)用的時機無關(guān)²⁰。最后，對一項卒中注冊實驗（RESCUE Japan Registry[Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism]）的亞類分析提示，依達拉奉聯(lián)用r-tPA比MT更有效21。

URICO-ICTUS（Efficacy Study of Combined Treatment With Uric Acid and r-tPA in Acute Ischemic Stroke）實驗評價尿酸聯(lián)用r-tPA/MT對急性IS的治療效果，確定在發(fā)病4.5小時的時間窗內(nèi)是安全的。此研究也報告，尿酸降低梗塞發(fā)展，改善早期再通和高血糖患者的結(jié)局¹⁶。有研究也證實了尿酸聯(lián)用MT的有效性²²。

治療性亞低溫，被認為可靶向多種R/I機制，也顯示可改善心臟驟停和新生兒缺血缺氧的神經(jīng)功能結(jié)局⁵⁷。在實驗性tMCAO，治療性亞低溫與r-tPA聯(lián)用可減少BBB破壞和HTf¹⁸。ReCCLAIM（Reperfusion and Cooling in Cerebral Acute Ischemia）²³和ICTuS-2（Intravascular Cooling in the Treatment of Stroke 2）²⁴檢驗卒中患者中這種治療組合，均顯示這種治療組合是安全可行的，盡管RECCLAIM-Ⅱ（進一步檢驗MT）因為缺乏資金支持而提前終止²⁵。MT與經(jīng)動脈內(nèi)注入冷鹽水聯(lián)用而選擇性腦降溫的初步研究正在進行，顯示是安全可行的⁵⁸。

ACTION-1（Effect of Natalizumab on Infarct Volume in Acute Ischemia Stroke）研究那他珠單抗在急性IS中的安全和有效性。那他珠單抗是整合素α4的抗體，用于治療多發(fā)性硬化。那他珠單抗被認為可減少淋巴細胞浸潤和黏附分子上調(diào)。雖然那他珠單抗在實驗性卒中未顯示有效性⁵⁹，ACTION-1包含接受r-tPA的患者⁶⁰。雖然給那他珠單抗后梗塞體積無顯著差異，但神經(jīng)系統(tǒng)結(jié)局有改善。

其它的抗炎和抗氧化藥物（均在臨床上用于其它適應(yīng)癥）也在臨床上與r-tPA聯(lián)用。Ⅰ期實驗SAVER-1（Superselective Administration of VErapamil During Recanalization in Acute Ischemic Stroke）研究維拉帕米聯(lián)合r-tPA/MT的治療效果，發(fā)現(xiàn)此組合安全²⁶。類似的，米諾環(huán)素聯(lián)用r-tPA也看起來是安全的，雖然效果不明確²⁷。表沒食子兒茶素沒食子酸酯聯(lián)用r-tPA看起來可延長r-tPA的治療時間窗并改善結(jié)局²⁸。一項小型研究提示，口服芬戈莫德能安全地改善90天神經(jīng)功能結(jié)局⁶¹。同時，一項芬戈莫德聯(lián)用r-tPA的初步研究證實，其安全和趨向良好臨床結(jié)局，減少HTf²⁹。近期，Ⅳ期實驗STARS07（Stroke Treatment with Acute Reperfusion and Simvastatin）證實了辛伐他汀在治療急性卒中的有效性和安全性，顯示辛伐他汀聯(lián)用r-tPA安全且可減少HTf³⁰。

目前，有幾項正在進行的旨在評價血管再通聯(lián)合神經(jīng)保護安全性和有效性的研究。與先前實驗相比，這些研究直接檢驗輔助治療聯(lián)合r-tPA/MT是否改善結(jié)局，同時也可以研究R/I?；罨鞍證被認為可抑制炎癥并阻止BBB破壞，在RHAPSODY（The Safety Evaluation of 3K3A-activated protein C in Ischemic Stroke）（NCT02222714）中正與r-tPA/MT聯(lián)合應(yīng)用⁶²。

另一項阿托伐他汀與MT聯(lián)用的臨床研究SEATIS（The Safety and Efficacy Study of High Dose Atorvastatin After Thrombolytic Treatment in Acute Ischemic Stroke）（NCT02452502）也在進行中⁶³。NA-1聯(lián)合MT的ESCAPE-NA1（Safety and Efficacy of NA-1 in Subjects Undergoing Endovascular Thrombectomy for Stroke）（NCT02930018）旨在評價安全性和有效性。雖然并未限制招募接受r-tPA/MT治療的患者，ACTIONⅡ（NCT02730455）評價靜脈用那他珠單抗的安全性和有效性。

最后，F(xiàn)AMTAIS（Fingolimod with Alteplase bridging with Mechanical Thrombectomy in Acute Ischemic Stroke;NCT02956200）作為一項Ⅱ期橋接療法（fingolimod聯(lián)合r-tPA/MT），近期開始評估在大血管堵塞中的安全性和有效性⁶⁴。

對急性卒中R/I的廣泛研究有可能找到可向臨床轉(zhuǎn)化的潛在治療靶點。R/I現(xiàn)象在實驗室已經(jīng)有較好的研究。雖然在臨床上不清楚，急性血管再通的新進展可能幫助明確人類是否存在R/I。盡管藥物溶栓有增加腦出血的風(fēng)險，針對同一靶標(biāo)的輔助治療在實驗條件下可減少HTf，延長治療時間窗和改善結(jié)局。我們推測這些治療也能使更多的卒中患者適合血管再通治療。

侯坤，吉林大學(xué)第一醫(yī)院神經(jīng)外科

李桂晨，吉林大學(xué)第一醫(yī)院神經(jīng)內(nèi)科

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