炎症反应与缺血性脑卒中后出血转换

麦鸿成，陈丹霞，徐炳东，张玉生

(暨南大学第一附属医院神经内科，广东 广州 510632)

·综 述·

炎症反应与缺血性脑卒中后出血转换

麦鸿成，陈丹霞，徐炳东，张玉生

(暨南大学第一附属医院神经内科，广东 广州 510632)

缺血性脑卒中后出血转换(HT)是一种常见脑血管疾病并发症，较一般缺血性脑卒中有更高的致残率及病死率。目前文献报道，炎症反应是导致HT发生及加重的原因，其可通过参与氧化应激、激活基质金属蛋白酶、堆积炎症因子及血管异常生成等各方面起作用。本文就炎症反应参与HT发生的机制进行综述。

炎症反应；缺血；脑卒中；出血转换

炎症反应是由外源性和内源性刺激导致机体产生非特异性的抵抗反应。缺血性卒中后引发的炎症日益引起研究者重视，其或许在脑组织再次损害及梗死程度加深起关键作用[1]。缺血性脑卒中引起的炎症反应是以脑血管内白细胞被激活、一系列炎症介质增加与血管异常反应为特点的炎症反应[2]。近年来越来越多的证据表明缺血性脑卒中引起的炎症反应对临床预后中有重要价值，尤其与其继发性损害——出血转换(hemorrhagic transformation，HT)密切相关。

HT是缺血性脑卒中的一种常见并发症，表现为梗死区域血管重新恢复血流灌注后出现继发性出血，出血既可在梗死区内，也可在远隔梗死区的部位发生，其在缺血性脑卒中患者的发生率为10%～40%[3]。

目前临床上针对HT的分型为：小点状出血(HI1)、多个融合的点状出血(HI2)、小的脑实质出血(PH1)(＜30%梗死灶，轻微占位效应)、大的脑实质出血(PH2)(＞30%梗死灶，明显占位效应)[4]。根据神经功能恶化的表现(National Institutes of Health Stroke Scale，缺血性卒中发生36 h内NIHSS评分增加4分)，HT可分为症状性颅内出血与非症状性颅内出血[5]。即使是无症状性颅内出血，也能造成不良的卒中预后，预防HT发生对缺血性脑卒中患者大有裨益[6]。然而，临床上HT的分型并不能完整体现HT的病理生理学变化过程，尤其是早期HT的发生，这给HT的防治增加了困难。

现已证实，血脑屏障(blood-brain barrier，BBB)受到破坏是导致HT发生，进而影响HT发生后患者神经功能、甚至死亡的主要病理生理学机制。缺血性脑卒中发生后引起的炎症反应通过氧化应激作用、基质金属蛋白酶作用、炎症因子堆积及血管异常生成对BBB损伤是导致HT发生的重要因素[7]。目前为止，不少学者针对HT发生过程中可能涉及炎症反应的发病因素开展了大量研究，本文现就炎症反应参与HT发生的机制做一综述，以期为临床上更好防治HT的提供参考。

1 氧化应激

相关报道证实氧化应激在HT的发生起重要作用。缺血性卒脑中后的缺血期及缺血再灌注期均促进炎症因子的聚集，减少体内谷胱甘肽的合成，加剧氧化应激反应[8]。缺血再灌注过程中氧化应激产生活性氧(reactive oxygen species，ROS)等一系列的损伤因子破坏血脑屏障，在HT发生扮演重要角色[9]。ROS大部分由中性粒细胞及巨噬细胞内的吞噬细胞氧化酶复合体，包括细胞内线粒体、NADPH(nicotinamide adenine dinucleotide phosphate，NADPH)[10]、氧化酶、黄嘌呤氧化酶、细胞膜受体等产生[11]，且其发挥损伤作用的时候需要中性粒细胞参与。缺血缺氧性损害时炎症因子活性增加，ROS产生相应增加[12]，造成神经血管单元的内皮细胞、周细胞、平滑肌细胞、星形胶质细胞的破坏，进一步导致血脑屏障通透性的增加[13-14]。ROS在激活大脑中动脉栓塞(middle cerebral artery occlusion,MCAO)后大鼠点样受体蛋白炎症通路也起一定作用[15]。动物体内实验发现抑制脑梗死后炎症因子的表达及中性粒细胞的活化，可减轻ROS的产生，维持血脑屏障完整，从而降低HT的发生率[16]。

氧化应激还可以进一步触发其他炎症通路激活，如核转录因子kappaB(nuclear factor kappa-light-chain-enhancer of activated B cells，NFκB)、活化蛋白(activator protein，AP-1)等相关信号通路的激活，从而增加基质金属蛋白酶9(matrix metalloproteinases，MMP9)的表达及影响DNA修复酶，触发凋亡始发P38-丝裂原(P38-mitogen activated protein kinase，P38-MAPK)通路活化，促进内皮细胞凋亡，增加血脑屏障通透性[17-18]。

2 基质金属蛋白酶(matrix metalloproteinases，MMPs)激活

细胞外基质对于维持血脑屏障的稳定至关重要，而缺血性脑卒中后炎症相关的免疫系统迅速激活，通过白细胞黏附、聚集及迁移，经单核-巨噬系统，释放肿瘤坏死因子α (tumor necrosis factor α，TNF-α)、白介素-1(interleukin-1，IL-1)和IL6等炎性介质[19]，激发一系列炎症相关信号途径，促进MMPs分泌，加速机体细胞外基质的溶解，进一步外渗白细胞，产生更多炎性介质，从而形成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，都作为BBB异常开放及HT发生的基质蛋白水解酶[22]，可从血管腔侧直接降解紧密连接蛋白或经内皮细胞吞噬后，作用于血管基膜和BBB相关基质(IV型基膜胶原、纤连蛋白和层黏连蛋白)，最终破坏内皮细胞、周细胞与星形胶质细胞连接，促进HT发生[23-24]。同时大量活化的白细胞通过破损的BBB渗入到脑实质内，释放更多炎症介质，加速神经元的损伤[25-26]。

在缺血性卒中发生后的2～8 h，人体外周血MMP-9会出现一个短暂高峰，一个重要原因是炎症反应后白细胞数量增加[27]。实验发现敲除嵌合体小鼠的白细胞MMP-9基因后，BBB破坏减轻，而MMP-9裸鼠经野生型(MMP-9基因完好)骨髓移植后，经过短暂MCAO后，接近野生型小鼠的BBB破损程度及梗死体积[28]。这提示，BBB破损的一个重要因素是白细胞分泌的MMP-9。

在缺血性卒中发生后的炎症反应，MMP-9主要来自中性粒细胞，降低中性粒细胞数量及减弱其功能可以减轻BBB的破损及HT的发生率。当使用长春新碱、对抗中性粒细胞抗体或CD11b/CD18拮抗剂，发现在啮齿类动物HT发生率降低[29]。通过炎症诱导剂脂多糖增加及激活中性粒细胞，BBB缺损明显[30]。来自中性粒细胞MMP-9的两种形式(95kDa单体与二聚体)与Ⅳ型基膜胶原降解、BBB发生密切相关[31]。缺血性脑卒中后外周血单核细胞作用于内皮细胞，通过炎症相关通路——趋化因子受体-2进入脑内分化为巨噬细胞并产生部分MMP-9[32]。

脑缺血卒中后，MMP-9可通过以下炎症相关机制活化：(1)ROS[18,33]；(2)TNF、IL-1等相关炎症介质引起MMP-3活化，导致前体MMP-9剪切成MMP-9[34]；(3)炎症因子—高迁移率族蛋白(high-mobility-group-box-1，HMGB1)通过TLR4受体诱导MMP-9活化[35]；(4)NF-κB炎症途径[36-37]。

缺血性脑卒中后体内释放以TNF-α及IL-6为代表的早期炎症介质[38]，刺激脑源性MMP-2合成及分泌[39]。MMP-2在缺血性卒中1～3 h开始升高，持续数天高于正常值，其在早期BBB破裂及HT发生起主要作用[39]。此外，对啮齿类动物脑部进行MM-2直接注射，可引起脑出血[40]。

有报道提示缺血性脑卒中后相关炎症导致MMP-3增加，MMP-3主要诱导前体MMP-9剪切成MMP-9，间接促使HT发生[34]。tPA结合LRP或炎症相关转录因子NF-κB增加MMP-3活性[41]。LPS促使小鼠颅脑炎症后，MMP-3表达增加，BBB破坏明显[42]。

3 炎症因子堆积

缺血性脑卒中后细胞来源的炎症因子也涉及HT的发生[43-44]。目前报道与HT发生相关的有：转化生长因子(transforming growth factor-beta1，TGF-β)、IL-1 β、双调蛋白和血管内皮生长因子。最近研究表明，炎症情况下TGF-β协助维护BBB完整。在大鼠MCAO后rt-PA诱发出血转换模型，TGF-β可降低MMP-2，MMP-9的表达，减轻基膜的损害，同时提高纤溶酶原抑制受体(plasminogen activator inhibitor type-1，PAI-1)及IV型胶原的表达[45]。轻型缺血性卒中小鼠外周血IL-1β发生改变，造成颅内紧密连接蛋白、claudin-5下降及中性粒细胞来源的MMP-9含量上升，BBB破坏程度加深，进一步诱导HT发生，从而导致脑组织损害、脑功能缺失及脑水肿[46]。临床试验发现，急性期第一天及第二天当中，HT患者相对普通缺血性脑卒中患者，外周血IL-1β升高，这一现象有助于预测HT发生[47]。双调蛋白通过MAP蛋白激酶信号通路，调节钙粘蛋白-E，从而改变内皮连接，增强中性粒细胞迁移，增加MMP-9和血管内皮生长因子释放，从而促进HT发生[43,48]。

4 血管异常生成

炎症反应和血管重塑是两个相互联系及共同发展的病理过程。新生血管及神经血管单元分泌一系列的生长因子促进原有血管形成侧枝及新生血管融入原有血管[49]。在血管异常生成期间，新生血管屏蔽作用及完整性下降，潜在提高HT发生率。

血管内皮生长因子在血管重塑及再生中起重要作用，其表现为双向作用，早期促使BBB破损，HT增加，晚期恢复BBB完整及功能[50]。早期降低血管内皮生长因子表达，可减少啮齿类动物HT发生[5-52]。相反，当缺血性脑卒中1 h后，使用血管内皮生长因子，可增加梗死体积、BBB受损发生率。而晚期缺血性脑卒中3～21 h后使用血管内皮生长因子，可使神经功能好转、周细胞贴附脑毛细血管更紧密及脑血流增加[53]。血管生成素对迟发性HT起作用。缺血性脑卒中患者血液中血管生成素含量升高，同时tPA相关HT发生风险增加。其中血管生成素-1对梗死区域的BBB通透性有影响[54]。高迁移率族蛋白B1(high-mobility-group-box-1，HMGB1)作为一种晚期炎症因子，是星形胶质细胞分泌的损伤相关模式分子，作用于祖内皮细胞的HMGB1受体，涉及缺血性脑卒中后神经血管单元修复及梗死区域周围的血管生成，目前认为与HT患者预后相关[55]。

5 结 语

综上所述，炎症反应通过参与氧化应激过程、激活基质金属蛋白酶、堆积炎症因子及血管异常生成等各方面对HT的发生以及发展具有重要影响，但其他潜在机制有待进一步研究。炎症反应与HT发生关系确切，然而目前临床医学在该邻域的药物开发偏少，今后的研究还需逐步开展具有治疗应用价值的相关药物。

[1]Mukandala G,Tynan R,Lanigan S,et al.The effects of hypoxia and inflammation on synaptic signaling in the CNS[J].Brain Sci,2016,6(1):E6.

[2] Dziedzic T.Systemic inflammation as a therapeutic target in acute ischemic stroke[J].Expert Rev Neurother,2015,15(5):523-531.

[3]Terruso V,D'Amelio M,Di Benedetto N,et al.Frequency and determinants for hemorrhagic transformation of cerebral infarction[J].Neuroepidemiology,2009,33(3):261-265.

[4]Beslow LA,Smith SE,Vossough A,et al.Hemorrhagic transformation of childhood arterial ischemic stroke[J].Stroke,2011,42(4):941-946.

[5]Hacke W,Kaste M,Bluhmki E,et al.Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke[J].N Engl J Med,2008,359(13):1317-1329.

[6]Dzialowski I,Pexman JH,Barber PA,et al.Asymptomatic hemorrhage after thrombolysis may not be benign:prognosis by hemorrhage type in the Canadian alteplase for stroke effectiveness study registry[J].Stroke,2007,38(1):75-79.

[7]Park JH,Ko Y,Kim WJ,et al.Is asymptomatic hemorrhagic transformation really innocuous?[J].Neurology,2012,78(6):421-426.

[8]Ravindran J,Agrawal M,Gupta N,et al.Alteration of blood brain barrier permeability by T-2 toxin:Role of MMP-9 and inflammatory cytokines[J].Toxicology,2011,280(1-2):44-52.

[9]Tang XN,Zheng Z,Giffard RG,et al.Significance of marrow-derived nicotinamide adenine dinucleotide phosphate oxidase in experimental ischemic stroke[J].Ann Neurol,2011,70(4):606-615.

[10]Tuo YH,Liu Z,Chen JW,et al.NADPH oxidase inhibitor improves outcome of mechanical reperfusion by suppressing hemorrhagic transformation[J].J Neurointerv Surg,2017,9(5):492-498.

[11]Fraser,PA.The role of free radical generation in increasing cerebrovascular permeability[J].Free Radic Biol Med,2011,51(5):967-977.

[12]Pober JS,Min W,Bradley JR.Bradley,Mechanisms of endothelial dysfunction,injury,and death[J].Annu Rev Pathol,2009,4:71-95.

[13]Alluri H,Stagg HW,Wilson RL,et al.Reactive oxygen species-caspase-3 relationship in mediating blood-brain barrier endothelial cell hyperpermeability following oxygen-glucose deprivation and reoxygenation[J].Microcirculation,2014,21(2):187-195.

[14]McLaughlin B,Hartnett KA,Erhardt JA,et al.Caspase 3 activation is essential for neuroprotection in preconditioning[J].Proc Natl Acad Sci U SA,2003,100(2):715-720.

[15]Guo ZN,Xu L,Hu Q,et al.Hyperbaric oxygen preconditioning attenuates hemorrhagic transformation through reactive oxygen species/thioredoxin-interacting protein/Nod-like receptor protein 3 pathway in hyperglycemic middle cerebral artery occlusion rats[J].Crit Care Med,2016,44(6):e403-e411.

[16]Asahi M,Asahi K,Wang X,et al.Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats[J].J Cereb Blood Flow Metab,2000,20(3):452-457.

[17]Sironi L,Banfi C,Brioschi M,et al.Activation of NF-κB and ERK1/2 after permanent focal ischemia is abolished by simvastatin treatment[J].Neurobiol Dis,2006,22(2):445-451.

[18]Kelly PJ,Morrow JD,Ning M,et al.Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke:the Biomarker Evaluation for Antioxidant Therapies in Stroke(BEAT-Stroke)study[J].Stroke,2008.39(1):100-104.

[19]Watters O,O'Connor JJ.A role for tumor necrosis factor-alpha in ischemiaandischemicpreconditioning[J].J Neuroinflammation,2011,8:87.

[20]Kato H,Duarte S,Liu D,et al.Matrix metalloproteinase-2(MMP-2)gene deletion enhances MMP-9 activity,impairs PARP-1 degradation,and exacerbates hepatic ischemia and reperfusion injury in mice[J].PLoS One,2015,10(9):e0137642.

[21]Fan Z,Yao J,Li Y,et al.Anti-inflammatory and antioxidant effects of curcumin on acute lung injury in a rodent model of intestinal ischemia reperfusion by inhibiting the pathway of NF-κB[J].Int J Clin Exp Pathol,2015,8(4):3451-3459.

[22]Visse R,Nagase H.Matrix metalloproteinases and tissue inhibitors of metalloproteinases:structure,function,and biochemistry[J].Circ Res,2003.92(8):827-839.

[23]Kalela A,Pönniö M,Koivu TA,et al.Association of serum sialic acid and MMP-9 with lipids and inflammatory markers[J].Eur J Clin Invest,2000,30(2):99-104.

[24]Kuyvenhoven JP,Molenaar IQ,Verspaget HW,et al.Plasma MMP-2 and MMP-9 and their inhibitors TIMP-1 and TIMP-2 during human orthotopic liver transplantation.The effect of aprotinin and the relation to ischemia/reperfusion injury[J].Thromb Haemost,2004,91(3):506-513.

[25]Lu A,Clark JF,Broderick JP,et al.Reperfusion activates metalloproteinases that contribute to neurovascular injury[J].Exp Neurol,2008,210(2):549-559.

[26]Harris AK,Ergul A,Kozak A,et al.Effect of neutrophil depletion on gelatinase expression,edema formation and hemorrhagic transformation after focal ischemic stroke[J].BMC Neurosci,2005,6:49.

[27]Turner RJ,Sharp FR.Implications of MMP9 for blood brain barrier disruption and hemorrhagic transformation following ischemic stroke[J].Front Cell Neurosci,2016,10:56.

[28]Wang G,Guo Q,Hossain M,et al.Bone marrow-derived cells are the major source of MMP-9 contributing to blood-brain barrier dysfunction and infarct formation after ischemic stroke in mice[J].Brain Res,2009,1294:183-192.

[29]Gautier S,Ouk T,Petrault O,et al.Neutrophils contribute to intracerebral haemorrhages after treatment with recombinant tissue plasminogen activator following cerebral ischaemia[J].Br J Pharmacol,2009,156(4):673-679.

[30]Pétrault O,Ouk T,Gautier S,et al.Pharmacological neutropenia prevents endothelial dysfunction but not smooth muscle functions impairment induced by middle cerebral artery occlusion[J].Br J Pharmacol,2005,144(8):1051-1058.

[31]Justicia C,Panés J,Solé S,et al.Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats[J].J Cereb Blood Flow Metab,2003,23(12):1430-1440.

[32]Rosell A,Cuadrado E,Ortega-Aznar A,et al.MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina typeⅣcollagen degradation during hemorrhagic transformation after human ischemic stroke[J].Stroke,2008,39(4):1121-1126.

[33]Yang Y,Rosenberg GA.Blood-brain barrier breakdown in acute and chronic cerebrovascular disease[J].Stroke,2011,42(11):3323-3328.

[34]Hafez S,Abdelsaid M,El-Shafey S,et al.Matrix metalloprotease 3 exacerbates hemorrhagic transformation and worsens functional outcomes in hyperglycemic stroke[J].Stroke,2016,47(3):843-851.

[35]Qiu J,Xu J,Zheng Y,et al.High-mobility group box 1 promotes metalloproteinase-9 upregulation through Toll-like receptor 4 after cerebral ischemia[J].Stroke,2010,41(9):2077-2082.

[36]Wang L,Li Z,Zhang X,et al.Protective effect of shikonin in experimental ischemic stroke:attenuated TLR4,p-p38MAPK,NF-kappaB,TNF-alpha and MMP-9 expression,up-regulated claudin-5 expression,ameliorated BBB permeability[J].Neurochem Res,2014,39(1):97-106.

[37]Shih RH,Wang CY,Yang CM.NF-kappaB signaling pathways in neurological inflammation:a mini review[J].Front Mol Neurosci,2015,8:77.

[38]Dittmar M,Kiourkenidis G,Horn M,et al.Cerebral ischemia,matrix metalloproteinases,and TNF-alpha:MMP inhibitors may act not exclusively by reducing MMPactivity[J].Stroke,2004,35(7):e338-e340.

[39]del Zoppo GJ,Frankowski H,Gu YH,et al.Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation[J].J Cereb Blood Flow Metab,2012,32(5):919-932.

[40]Lo EH,Wang X,Cuzner ML.Extracellular proteolysis in brain injury and inflammation:role for plasminogen activators and matrix metalloproteinases[J].J Neurosci Res,2002,69(1):1-9.

[41]Suzuki Y,Nagai N,Yamakawa K,et al.Tissue-type plasminogen activator(t-PA)induces stromelysin-1(MMP-3)in endothelial cells through activation of lipoprotein receptor-related protein[J].Blood,2009,114(15):3352-3358.

[42]Walker EJ,Rosenberg GA.Rosenberg,TIMP-3 and MMP-3 contribute to delayed inflammation and hippocampal neuronal death following global ischemia[J].Exp Neurol,2009,216(1):122-131.

[43]Jickling GC,Ander BP,Stamova B,et al.RNA in blood is altered prior to hemorrhagic transformation in ischemic stroke[J].Ann Neurol,2013,74(2):232-240.

[44]Gliem M,Mausberg AK,Lee JI,et al.Macrophages prevent hemorrhagic infarct transformation in murine stroke models[J].Ann Neurol,2012,71(6):743-752.

[45]Cai Y,Liu X,Chen W,et al.TGF-beta1 prevents blood-brain barrier damage and hemorrhagic transformation after thrombolysis in rats[J].Exp Neurol,2015,266:120-126.

[46]McColl BW,Rothwell NJ,Allan SM.Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice[J].J Neurosci,2008.28(38):9451-9462.

[47]Nikiforova Postnikova TA,Doronin BM,Peskov SA.Blood serum cytokines as predictors of hemorrhagic transformation of ischemic stroke[J].Zh Nevrol Psikhiatr Im S S Korsakova,2014,114(3 pt 2):20-26.

[48]Zhan L,Zheng L,Hosoi T,et al.Stress-induced neuroprotective effects of epiregulin and amphiregulin[J].PLoS One,2015,10(2):e0118280.

[49]Durukan A,Marinkovic I,Strbian D,et al.Post-ischemic blood-brain barrier leakage in rats:one-week follow-up by MRI[J].Brain Res,2009,1280:158-165.

[50]Zechariah A,ElAli A,Doeppner TR,et al.Vascular endothelial growth factor promotes pericyte coverage of brain capillaries,improves cerebral blood flow during subsequent focal cerebral ischemia,and preserves the metabolic penumbra[J].Stroke,2013,44(6):1690-1697.

[51]Chen C,Ostrowski RP,Zhou C,et al.Suppression of hypoxia-inducible factor-1alpha and its downstream genes reduces acute hyperglycemia-enhanced hemorrhagic transformation in a rat model of cerebral ischemia[J].J Neurosci Res,2010,88(9):2046-2055.

[52]Kanazawa M,Igarashi H,Kawamura K,et al.Inhibition of VEGF signaling pathway attenuates hemorrhage after tPA treatment[J].J Cereb Blood Flow Metab,2011,31(6):1461-1474.

[53]Abumiya T,Yokota C,Kuge Y,et al.Aggravation of hemorrhagic transformation by early intraarterial infusion of low-dose vascular endothelial growth factor after transient focal cerebral ischemia in rats[J].Brain Res,2005,1049(1):95-103.

[54]Zhang ZG,Zhang L,Tsang W,et al.Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia[J].J Cereb Blood Flow Metab,2002,22(4):379-392.

[55]Hayakawa K,Pham LD,Katusic ZS,et al.Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery[J].Proc Natl Acad Sci USA,2012,109(19):7505-7510.

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

国家自然科学基金资助项目(编号：81171084)；广东省自然科学基金资助项目(编号：2014A030313384)；广东省医学科研基金资助项目(编号：A2014381)；广州市科技计划资助项目(编号：1561000289，155700029)

张玉生。E-mail：zhangys@jnu.edu.cn

2017-04-13)