炎癥反應與缺血性腦卒中后出血轉換

麥鴻成，陳丹霞，徐炳東，張玉生

(暨南大學第一附屬醫(yī)院神經內科，廣東 廣州 510632)

·綜 述·

炎癥反應與缺血性腦卒中后出血轉換

麥鴻成，陳丹霞，徐炳東，張玉生

(暨南大學第一附屬醫(yī)院神經內科，廣東 廣州 510632)

缺血性腦卒中后出血轉換(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，炎癥反應是導致HT發(fā)生及加重的原因，其可通過參與氧化應激、激活基質金屬蛋白酶、堆積炎癥因子及血管異常生成等各方面起作用。本文就炎癥反應參與HT發(fā)生的機制進行綜述。

炎癥反應；缺血；腦卒中；出血轉換

炎癥反應是由外源性和內源性刺激導致機體產生非特異性的抵抗反應。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鍵作用[1]。缺血性腦卒中引起的炎癥反應是以腦血管內白細胞被激活、一系列炎癥介質增加與血管異常反應為特點的炎癥反應[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對臨床預后中有重要價值，尤其與其繼發(fā)性損害——出血轉換(hemorrhagic transformation，HT)密切相關。

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)域血管重新恢復血流灌注后出現(xiàn)繼發(fā)性出血，出血既可在梗死區(qū)內，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)、小的腦實質出血(PH1)(＜30%梗死灶，輕微占位效應)、大的腦實質出血(PH2)(＞30%梗死灶，明顯占位效應)[4]。根據(jù)神經功能惡化的表現(xiàn)(National Institutes of Health Stroke Scale，缺血性卒中發(fā)生36 h內NIHSS評分增加4分)，HT可分為癥狀性顱內出血與非癥狀性顱內出血[5]。即使是無癥狀性顱內出血，也能造成不良的卒中預后，預防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)受到破壞是導致HT發(fā)生，進而影響HT發(fā)生后患者神經功能、甚至死亡的主要病理生理學機制。缺血性腦卒中發(fā)生后引起的炎癥反應通過氧化應激作用、基質金屬蛋白酶作用、炎癥因子堆積及血管異常生成對BBB損傷是導致HT發(fā)生的重要因素[7]。目前為止，不少學者針對HT發(fā)生過程中可能涉及炎癥反應的發(fā)病因素開展了大量研究，本文現(xiàn)就炎癥反應參與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 氧化應激

相關報道證實氧化應激在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，減少體內谷胱甘肽的合成，加劇氧化應激反應[8]。缺血再灌注過程中氧化應激產生活性氧(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的吞噬細胞氧化酶復合體，包括細胞內線粒體、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產生相應增加[12]，造成神經血管單元的內皮細胞、周細胞、平滑肌細胞、星形膠質細胞的破壞，進一步導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的產生，維持血腦屏障完整，從而降低HT的發(fā)生率[16]。

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

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

細胞外基質對于維持血腦屏障的穩(wěn)定至關重要，而缺血性腦卒中后炎癥相關的免疫系統(tǒng)迅速激活，通過白細胞黏附、聚集及遷移，經單核-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[19]，激發(fā)一系列炎癥相關信號途徑，促進MMPs分泌，加速機體細胞外基質的溶解，進一步外滲白細胞，產生更多炎性介質，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)生的基質蛋白水解酶[22]，可從血管腔側直接降解緊密連接蛋白或經內皮細胞吞噬后，作用于血管基膜和BBB相關基質(IV型基膜膠原、纖連蛋白和層黏連蛋白)，最終破壞內皮細胞、周細胞與星形膠質細胞連接，促進HT發(fā)生[23-24]。同時大量活化的白細胞通過破損的BBB滲入到腦實質內，釋放更多炎癥介質，加速神經元的損傷[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裸鼠經野生型(MMP-9基因完好)骨髓移植后，經過短暫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，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[31]。缺血性腦卒中后外周血單核細胞作用于內皮細胞，通過炎癥相關通路——趨化因子受體-2進入腦內分化為巨噬細胞并產生部分MMP-9[32]。

腦缺血卒中后，MMP-9可通過以下炎癥相關機制活化：(1)ROS[18,33]；(2)TNF、IL-1等相關炎癥介質引起MMP-3活化，導致前體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MMP-9活化[35]；(4)NF-κB炎癥途徑[36-37]。

缺血性腦卒中后體內釋放以TNF-α及IL-6為代表的早期炎癥介質[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炎癥導致MMP-3增加，MMP-3主要誘導前體MMP-9剪切成MMP-9，間接促使HT發(fā)生[34]。tPA結合LRP或炎癥相關轉錄因子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)生相關的有：轉化生長因子(transforming growth factor-beta1，TGF-β)、IL-1 β、雙調蛋白和血管內皮生長因子。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HT發(fā)生，從而導致腦組織損害、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)象有助于預測HT發(fā)生[47]。雙調蛋白通過MAP蛋白激酶信號通路，調節(jié)鈣粘蛋白-E，從而改變內皮連接，增強中性粒細胞遷移，增加MMP-9和血管內皮生長因子釋放，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。新生血管及神經血管單元分泌一系列的生長因子促進原有血管形成側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BBB完整及功能[50]。早期降低血管內皮生長因子表達，可減少嚙齒類動物HT發(fā)生[5-52]。相反，當缺血性腦卒中1 h后，使用血管內皮生長因子，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后使用血管內皮生長因子，可使神經功能好轉、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HT發(fā)生風險增加。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，是星形膠質細胞分泌的損傷相關模式分子，作用于祖內皮細胞的HMGB1受體，涉及缺血性腦卒中后神經血管單元修復及梗死區(qū)域周圍的血管生成，目前認為與HT患者預后相關[55]。

5 結 語

綜上所述，炎癥反應通過參與氧化應激過程、激活基質金屬蛋白酶、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。炎癥反應與HT發(fā)生關系確切，然而目前臨床醫(yī)學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用價值的相關藥物。

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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

國家自然科學基金資助項目(編號：81171084)；廣東省自然科學基金資助項目(編號：2014A030313384)；廣東省醫(yī)學科研基金資助項目(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)