麥鴻成，陳丹霞，徐炳東，張玉生

(暨南大學(xué)第一附屬醫(yī)院神經(jīng)內(nèi)科，廣東 廣州 510632)

·綜 述·

炎癥反應(yīng)與缺血性腦卒中后出血轉(zhuǎn)換

麥鴻成，陳丹霞，徐炳東，張玉生

(暨南大學(xué)第一附屬醫(yī)院神經(jīng)內(nèi)科，廣東 廣州 510632)

缺血性腦卒中后出血轉(zhuǎn)換(HT)是一種常見腦血管疾病并發(fā)癥，較一般缺血性腦卒中有更高的致殘率及病死率。目前文獻報道，炎癥反應(yīng)是導(dǎo)致HT發(fā)生及加重的原因，其可通過參與氧化應(yīng)激、激活基質(zhì)金屬蛋白酶、堆積炎癥因子及血管異常生成等各方面起作用。本文就炎癥反應(yīng)參與HT發(fā)生的機制進行綜述。

炎癥反應(yīng)；缺血；腦卒中；出血轉(zhuǎn)換

炎癥反應(yīng)是由外源性和內(nèi)源性刺激導(dǎo)致機體產(chǎn)生非特異性的抵抗反應(yīng)。缺血性卒中后引發(fā)的炎癥日益引起研究者重視，其或許在腦組織再次損害及梗死程度加深起關(guān)鍵作用[1]。缺血性腦卒中引起的炎癥反應(yīng)是以腦血管內(nèi)白細胞被激活、一系列炎癥介質(zhì)增加與血管異常反應(yīng)為特點的炎癥反應(yīng)[2]。近年來越來越多的證據(jù)表明缺血性腦卒中引起的炎癥反應(yīng)對臨床預(yù)后中有重要價值，尤其與其繼發(fā)性損害——出血轉(zhuǎn)換(hemorrhagic transformation，HT)密切相關(guān)。

HT是缺血性腦卒中的一種常見并發(fā)癥，表現(xiàn)為梗死區(qū)域血管重新恢復(fù)血流灌注后出現(xiàn)繼發(fā)性出血，出血既可在梗死區(qū)內(nèi)，也可在遠隔梗死區(qū)的部位發(fā)生，其在缺血性腦卒中患者的發(fā)生率為10%～40%[3]。

目前臨床上針對HT的分型為：小點狀出血(HI1)、多個融合的點狀出血(HI2)、小的腦實質(zhì)出血(PH1)(＜30%梗死灶，輕微占位效應(yīng))、大的腦實質(zhì)出血(PH2)(＞30%梗死灶，明顯占位效應(yīng))[4]。根據(jù)神經(jīng)功能惡化的表現(xiàn)(National Institutes of Health Stroke Scale，缺血性卒中發(fā)生36 h內(nèi)NIHSS評分增加4分)，HT可分為癥狀性顱內(nèi)出血與非癥狀性顱內(nèi)出血[5]。即使是無癥狀性顱內(nèi)出血，也能造成不良的卒中預(yù)后，預(yù)防HT發(fā)生對缺血性腦卒中患者大有裨益[6]。然而，臨床上HT的分型并不能完整體現(xiàn)HT的病理生理學(xué)變化過程，尤其是早期HT的發(fā)生，這給HT的防治增加了困難。

現(xiàn)已證實，血腦屏障(blood-brain barrier，BBB)受到破壞是導(dǎo)致HT發(fā)生，進而影響HT發(fā)生后患者神經(jīng)功能、甚至死亡的主要病理生理學(xué)機制。缺血性腦卒中發(fā)生后引起的炎癥反應(yīng)通過氧化應(yīng)激作用、基質(zhì)金屬蛋白酶作用、炎癥因子堆積及血管異常生成對BBB損傷是導(dǎo)致HT發(fā)生的重要因素[7]。目前為止，不少學(xué)者針對HT發(fā)生過程中可能涉及炎癥反應(yīng)的發(fā)病因素開展了大量研究，本文現(xiàn)就炎癥反應(yīng)參與HT發(fā)生的機制做一綜述，以期為臨床上更好防治HT的提供參考。

1 氧化應(yīng)激

相關(guān)報道證實氧化應(yīng)激在HT的發(fā)生起重要作用。缺血性卒腦中后的缺血期及缺血再灌注期均促進炎癥因子的聚集，減少體內(nèi)谷胱甘肽的合成，加劇氧化應(yīng)激反應(yīng)[8]。缺血再灌注過程中氧化應(yīng)激產(chǎn)生活性氧(reactive oxygen species，ROS)等一系列的損傷因子破壞血腦屏障，在HT發(fā)生扮演重要角色[9]。ROS大部分由中性粒細胞及巨噬細胞內(nèi)的吞噬細胞氧化酶復(fù)合體，包括細胞內(nèi)線粒體、NADPH(nicotinamide adenine dinucleotide phosphate，NADPH)[10]、氧化酶、黃嘌呤氧化酶、細胞膜受體等產(chǎn)生[11]，且其發(fā)揮損傷作用的時候需要中性粒細胞參與。缺血缺氧性損害時炎癥因子活性增加，ROS產(chǎn)生相應(yīng)增加[12]，造成神經(jīng)血管單元的內(nèi)皮細胞、周細胞、平滑肌細胞、星形膠質(zhì)細胞的破壞，進一步導(dǎo)致血腦屏障通透性的增加[13-14]。ROS在激活大腦中動脈栓塞(middle cerebral artery occlusion,MCAO)后大鼠點樣受體蛋白炎癥通路也起一定作用[15]。動物體內(nèi)實驗發(fā)現(xiàn)抑制腦梗死后炎癥因子的表達及中性粒細胞的活化，可減輕ROS的產(chǎn)生，維持血腦屏障完整，從而降低HT的發(fā)生率[16]。

氧化應(yīng)激還可以進一步觸發(fā)其他炎癥通路激活，如核轉(zhuǎn)錄因子kappaB(nuclear factor kappa-light-chain-enhancer of activated B cells，NFκB)、活化蛋白(activator protein，AP-1)等相關(guān)信號通路的激活，從而增加基質(zhì)金屬蛋白酶9(matrix metalloproteinases，MMP9)的表達及影響DNA修復(fù)酶，觸發(fā)凋亡始發(fā)P38-絲裂原(P38-mitogen activated protein kinase，P38-MAPK)通路活化，促進內(nèi)皮細胞凋亡，增加血腦屏障通透性[17-18]。

2 基質(zhì)金屬蛋白酶(matrix metalloproteinases，MMPs)激活

細胞外基質(zhì)對于維持血腦屏障的穩(wěn)定至關(guān)重要，而缺血性腦卒中后炎癥相關(guān)的免疫系統(tǒng)迅速激活，通過白細胞黏附、聚集及遷移，經(jīng)單核-巨噬系統(tǒng)，釋放腫瘤壞死因子α (tumor necrosis factor α，TNF-α)、白介素-1(interleukin-1，IL-1)和IL6等炎性介質(zhì)[19]，激發(fā)一系列炎癥相關(guān)信號途徑，促進MMPs分泌，加速機體細胞外基質(zhì)的溶解，進一步外滲白細胞，產(chǎn)生更多炎性介質(zhì)，從而形成BBB通透性增加的生化瀑布事件[20-21]。MMPs包括MMP-9、MMP-2和MMP-3，都作為BBB異常開放及HT發(fā)生的基質(zhì)蛋白水解酶[22]，可從血管腔側(cè)直接降解緊密連接蛋白或經(jīng)內(nèi)皮細胞吞噬后，作用于血管基膜和BBB相關(guān)基質(zhì)(IV型基膜膠原、纖連蛋白和層黏連蛋白)，最終破壞內(nèi)皮細胞、周細胞與星形膠質(zhì)細胞連接，促進HT發(fā)生[23-24]。同時大量活化的白細胞通過破損的BBB滲入到腦實質(zhì)內(nèi)，釋放更多炎癥介質(zhì)，加速神經(jīng)元的損傷[25-26]。

在缺血性卒中發(fā)生后的2～8 h，人體外周血MMP-9會出現(xiàn)一個短暫高峰，一個重要原因是炎癥反應(yīng)后白細胞數(shù)量增加[27]。實驗發(fā)現(xiàn)敲除嵌合體小鼠的白細胞MMP-9基因后，BBB破壞減輕，而MMP-9裸鼠經(jīng)野生型(MMP-9基因完好)骨髓移植后，經(jīng)過短暫MCAO后，接近野生型小鼠的BBB破損程度及梗死體積[28]。這提示，BBB破損的一個重要因素是白細胞分泌的MMP-9。

在缺血性卒中發(fā)生后的炎癥反應(yīng)，MMP-9主要來自中性粒細胞，降低中性粒細胞數(shù)量及減弱其功能可以減輕BBB的破損及HT的發(fā)生率。當(dāng)使用長春新堿、對抗中性粒細胞抗體或CD11b/CD18拮抗劑，發(fā)現(xiàn)在嚙齒類動物HT發(fā)生率降低[29]。通過炎癥誘導(dǎo)劑脂多糖增加及激活中性粒細胞，BBB缺損明顯[30]。來自中性粒細胞MMP-9的兩種形式(95kDa單體與二聚體)與Ⅳ型基膜膠原降解、BBB發(fā)生密切相關(guān)[31]。缺血性腦卒中后外周血單核細胞作用于內(nèi)皮細胞，通過炎癥相關(guān)通路——趨化因子受體-2進入腦內(nèi)分化為巨噬細胞并產(chǎn)生部分MMP-9[32]。

腦缺血卒中后，MMP-9可通過以下炎癥相關(guān)機制活化：(1)ROS[18,33]；(2)TNF、IL-1等相關(guān)炎癥介質(zhì)引起MMP-3活化，導(dǎo)致前體MMP-9剪切成MMP-9[34]；(3)炎癥因子—高遷移率族蛋白(high-mobility-group-box-1，HMGB1)通過TLR4受體誘導(dǎo)MMP-9活化[35]；(4)NF-κB炎癥途徑[36-37]。

缺血性腦卒中后體內(nèi)釋放以TNF-α及IL-6為代表的早期炎癥介質(zhì)[38]，刺激腦源性MMP-2合成及分泌[39]。MMP-2在缺血性卒中1～3 h開始升高，持續(xù)數(shù)天高于正常值，其在早期BBB破裂及HT發(fā)生起主要作用[39]。此外，對嚙齒類動物腦部進行MM-2直接注射，可引起腦出血[40]。

有報道提示缺血性腦卒中后相關(guān)炎癥導(dǎo)致MMP-3增加，MMP-3主要誘導(dǎo)前體MMP-9剪切成MMP-9，間接促使HT發(fā)生[34]。tPA結(jié)合LRP或炎癥相關(guān)轉(zhuǎn)錄因子NF-κB增加MMP-3活性[41]。LPS促使小鼠顱腦炎癥后，MMP-3表達增加，BBB破壞明顯[42]。

3 炎癥因子堆積

缺血性腦卒中后細胞來源的炎癥因子也涉及HT的發(fā)生[43-44]。目前報道與HT發(fā)生相關(guān)的有：轉(zhuǎn)化生長因子(transforming growth factor-beta1，TGF-β)、IL-1 β、雙調(diào)蛋白和血管內(nèi)皮生長因子。最近研究表明，炎癥情況下TGF-β協(xié)助維護BBB完整。在大鼠MCAO后rt-PA誘發(fā)出血轉(zhuǎn)換模型，TGF-β可降低MMP-2，MMP-9的表達，減輕基膜的損害，同時提高纖溶酶原抑制受體(plasminogen activator inhibitor type-1，PAI-1)及IV型膠原的表達[45]。輕型缺血性卒中小鼠外周血IL-1β發(fā)生改變，造成顱內(nèi)緊密連接蛋白、claudin-5下降及中性粒細胞來源的MMP-9含量上升，BBB破壞程度加深，進一步誘導(dǎo)HT發(fā)生，從而導(dǎo)致腦組織損害、腦功能缺失及腦水腫[46]。臨床試驗發(fā)現(xiàn)，急性期第一天及第二天當(dāng)中，HT患者相對普通缺血性腦卒中患者，外周血IL-1β升高，這一現(xiàn)象有助于預(yù)測HT發(fā)生[47]。雙調(diào)蛋白通過MAP蛋白激酶信號通路，調(diào)節(jié)鈣粘蛋白-E，從而改變內(nèi)皮連接，增強中性粒細胞遷移，增加MMP-9和血管內(nèi)皮生長因子釋放，從而促進HT發(fā)生[43,48]。

4 血管異常生成

炎癥反應(yīng)和血管重塑是兩個相互聯(lián)系及共同發(fā)展的病理過程。新生血管及神經(jīng)血管單元分泌一系列的生長因子促進原有血管形成側(cè)枝及新生血管融入原有血管[49]。在血管異常生成期間，新生血管屏蔽作用及完整性下降，潛在提高HT發(fā)生率。

血管內(nèi)皮生長因子在血管重塑及再生中起重要作用，其表現(xiàn)為雙向作用，早期促使BBB破損，HT增加，晚期恢復(fù)BBB完整及功能[50]。早期降低血管內(nèi)皮生長因子表達，可減少嚙齒類動物HT發(fā)生[5-52]。相反，當(dāng)缺血性腦卒中1 h后，使用血管內(nèi)皮生長因子，可增加梗死體積、BBB受損發(fā)生率。而晚期缺血性腦卒中3～21 h后使用血管內(nèi)皮生長因子，可使神經(jīng)功能好轉(zhuǎn)、周細胞貼附腦毛細血管更緊密及腦血流增加[53]。血管生成素對遲發(fā)性HT起作用。缺血性腦卒中患者血液中血管生成素含量升高，同時tPA相關(guān)HT發(fā)生風(fēng)險增加。其中血管生成素-1對梗死區(qū)域的BBB通透性有影響[54]。高遷移率族蛋白B1(high-mobility-group-box-1，HMGB1)作為一種晚期炎癥因子，是星形膠質(zhì)細胞分泌的損傷相關(guān)模式分子，作用于祖內(nèi)皮細胞的HMGB1受體，涉及缺血性腦卒中后神經(jīng)血管單元修復(fù)及梗死區(qū)域周圍的血管生成，目前認為與HT患者預(yù)后相關(guān)[55]。

5 結(jié) 語

綜上所述，炎癥反應(yīng)通過參與氧化應(yīng)激過程、激活基質(zhì)金屬蛋白酶、堆積炎癥因子及血管異常生成等各方面對HT的發(fā)生以及發(fā)展具有重要影響，但其他潛在機制有待進一步研究。炎癥反應(yīng)與HT發(fā)生關(guān)系確切，然而目前臨床醫(yī)學(xué)在該鄰域的藥物開發(fā)偏少，今后的研究還需逐步開展具有治療應(yīng)用價值的相關(guān)藥物。

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Inflammatory response and hemorrhagic transformation after cerebral ischemic stroke.

MAI Hong-cheng,CHEN Dan-xia,XU Bing-dong,ZHANG Yu-sheng.Department of Internal Neurology,the First Affiliated Hospital of Jinan University,Guangzhou 510632,Guangdong,CHINA

Hemorrhagic transformation(HT)after cerebral ischemic stroke,with higher morbidity and mortality than normal cerebral ischemic stroke,is a common complication of cerebrovascular diseases.At present,literatures report that inflammatory response is a cause of HT aggravation by participating in oxidative stress,matrix metalloproteinases activation,inflammatory mediator accumulation and vessel abnormal growth.Herein,we review the mechanism of inflammatory response in HT.

Inflammatory response;Stroke;Cerebral ischemic;Hemorrhagic transformation

R743.3

A

1003—6350（2017）22—3705—04

10.3969/j.issn.1003-6350.2017.22.029

國家自然科學(xué)基金資助項目(編號：81171084)；廣東省自然科學(xué)基金資助項目(編號：2014A030313384)；廣東省醫(yī)學(xué)科研基金資助項目(編號：A2014381)；廣州市科技計劃資助項目(編號：1561000289，155700029)

張玉生。E-mail：zhangys@jnu.edu.cn

2017-04-13)