耳蜗血管纹血-迷路屏障病理生理学研究进展

张桐 韩维举

北京解放军总医院耳鼻咽喉头颈外科（北京100853）

耳蜗血管纹血-迷路屏障病理生理学研究进展

张桐 韩维举

北京解放军总医院耳鼻咽喉头颈外科（北京100853）

血管纹和螺旋韧带位于耳蜗中阶外侧壁，其中血管纹的血-迷路屏障（blood-labyrinth barrier,BLB）是高度分化的毛细血管网，用于调控耳蜗血液和细胞间液的物质交换。此屏障保护内耳不接触来自血液的有毒物质，并且选择性的透过离子、液体及营养物质至耳蜗。血-迷路屏障对维持耳蜗内稳态有重要的作用。血迷路屏障结构上包括血管纹微血管内皮细胞（endothelial cells,ECs）、周细胞（pericytes,PCs）、血管周围巨噬细胞样黑色素细胞（perivascular residentmacrophage-likemelanocytes,PVM/Ms）、基膜（basementmembrance,BM）、复杂的紧密连接和黏合连接。ECs、PCs和PVM/Ms间的作用，类似于细胞间信号传导，对控制血管渗透性及为听功能提供适宜的环境起着至关重要的作用。在遗传缺陷、炎症、声损伤以及衰老的病理条件下，血-迷路屏障各组份间正常的相互作用遭到破坏，进而导致其通透性增加，引发听力障碍。

耳蜗；血管纹；血-迷路屏障；耳聋

Supported bythe NationalNatural Science Foundation ofChina(81170908,81470683).

Declaration of interest:Theauthors reportno conflictsof interest.

内耳是一个非常稳定的自体调节系统，通过血-迷路屏障（blood-labyrinth barrier,BLB）主动或被动转运离子、液体和营养物来维持其平衡状态[1-2]。正常功能的血管纹（指“血-迷路屏障”）对维持离子浓度和耳蜗内电位（EP）稳定有重要的作用[3-5]。血管纹BLB功能障碍是自身免疫性内耳疾病、噪声性聋、老年性聋和遗传性聋的原因之一[6-10]。本文综述血管纹BLB的病理生理学研究进展。

1 耳蜗血-迷路屏障的主要成分及结构

血管纹外接螺旋韧带位于耳蜗中阶外侧壁，主要包括基底细胞（basal cell,BC）、中间细胞（inter⁃mediate cell,IC）和边缘细胞（marginal cell,MC）[11]。BLB是一个特殊分化的毛细血管网，位于血管纹中间层。其结构包括内皮细胞（endothelial cells, ECs）、基膜（basementmembrane,BM）、周细胞（peri⁃cytes,PCs）[12]及血管周围巨噬细胞样黑色素细胞（perivascular residentmacrophage-like melanocytes, PVM/Ms）[13]。BLB通过紧密连接、膜屏障和化学作用控制离子、液体和营养物从血液循环进入血管纹[7、14]。

正常成年C57/6J小鼠耳蜗血-迷路屏障内存在约1220-1300个周细胞（PCs），形态上有很多足突，紧贴在血管纹毛细血管壁，嵌入到基膜内[6]。血管纹PCs表达血小板源内皮生长因子受体β（plate⁃let-derived growth factor receptor-β,PDGFR-β）、结蛋白（desmin）、神经/胶质抗原2（neural/glial anti⁃gen2,NG2）和CD90（胸腺抗原-1，Thy-1）[12]。血管纹PCs含有丰富的结蛋白，属于一种中间纤维蛋白质，可增强细胞构架机械强度且提高血管网物理弹性[12]。螺旋韧带PCs则更多表达收缩蛋白，如平滑肌肌动蛋白（α-SMA）和原肌球蛋白[12、15]。目前研究发现，PCs对血管生成、血流调节、血管完整性和组织纤维增生有重要作用[16]。PCs通过调节ECs间紧密连接蛋白的表达调控BLB的完整性[17]。体外细胞系3D共同培养实验研究发现PCs具有明显促进血管新生的作用[6]。非耳蜗组织中，PCs通过直接合成胶原蛋白IV(collagenIV)、粘多糖、纤维蛋白、巢蛋白-1、基底膜聚糖（串珠素，蛋白多糖）和层连粘蛋白促进基膜的形成[18]；抑制不稳定基质金属蛋白酶(MMP)的活性，如MMP-2和MMP-9[19-20]。正常成年C57/6J小鼠耳蜗的血-迷路屏障内存在一定数量的血管周围常驻巨噬样色素细胞(PVM/ Ms)[21]。多数观点认为PVM/Ms起源于耳蜗神经嵴黑色素细胞，随着发育迁移至耳蜗血管纹[22]。PVM/ Ms的位置极为贴近边缘细胞层下方，且多个足突与毛细血管管腔表面紧密接触。PVM/Ms是一种混合型细胞，具有巨噬细胞和黑色素细胞的特性[4]。早期研究发现，血管纹PVM/Ms表达一系列巨噬细胞表面抗原，包括F4/80、CD68和CD11b[13]。近期研究发现，PVM/Ms还具有黑素细胞的特性，包括含有大量的黑色素和表达黑素细胞标记蛋白，例如谷胱甘肽S-转移酶α4（Gatα4）和Kir4.1，后者为中间细胞的标记蛋白[4]。

ECs和PVM/Ms间的物理连接和信号传导调控BLB的完整性及稳定性[4]。PVM/Ms具有黑色素细胞的特性，为抵抗有害因素在局部组织生成黑色素[23]。黑色素通过缓冲钙，清除重金属、外源蛋白质及脂质，促进抗氧化活性而维持组织稳态[24]。血管纹PVM/Ms具有免疫防御及修复功能，例如：清除入侵的微生物及坏死细胞；PVM/Ms可作为免疫、炎性效应细胞产生超氧化物阴离子、一氧化氮和炎性因子[25-27]。一些研究认为，其他器官组织的固有巨噬细胞在组织受损修复时能够分化为成纤维细胞/成肌纤维细胞[28]。

BLB内基膜（BM）除主要包括胶原蛋白IV、层粘连蛋白、硫酸乙酰肝素蛋白多糖（HSPG）、巢蛋白和纤连蛋白外，还发现有β1和α1整合蛋白亚基[29-30]。BM中不同蛋白质相互作用形成均匀的致密板[31]。超微结构显示基膜蛋白聚糖呈多样化及模式化分布，且血管纹基膜带负电荷[32]。

2 血-迷路屏障的渗透性

动物实验发现幼年动物较成年动物的血管纹BLB渗透性更强。例如，Suzuki曾报道大鼠14日龄前其血管纹BLB未完全形成[33]。

主要通过细胞外和跨细胞两种途径控制血管纹BLB通透性。细胞外途径与内皮细胞间紧密连接蛋白瞬时状态相关。跨细胞途径包含吞饮和跨内皮渠道。BLB主要连接蛋白包括紧密连接蛋白occludin、claudins、zona occludens和黏合连接蛋白如钙粘素（VE-cadherin）[9、34]。近期实验表明紧密连接蛋白和黏合连接蛋白表达上调可提高屏障的完整性[4]。相反的，紧密连接蛋白和黏合连接蛋白表达下调可增加屏障的渗透性[4、34]。另外，跨细胞途径渗透率依赖于转运蛋白及转运通道。BLB中富含转运蛋白。例如，离体血管纹微血管质谱分析提示BLB中40%蛋白与转运蛋白相关[9]。

3 血-迷路屏障与听力障碍

BLB功能紊乱可导致听力出现障碍，如噪声性耳聋[35]、老年性耳聋[6]、自身免疫性疾病[36]、遗传性听力障碍[37]和炎性水肿[38]。此外，耳毒性药物也可通过BLB进入内耳，破坏听力功能。如顺铂类和氨基糖苷类药物[39]。尽管这些病理条件使BLB通透性和选择性发生改变，但是他们仍各自具有独特的特性。

3.1噪声性听力损伤（NIHL）

声损伤不但破坏感觉毛细胞、神经细胞和支持细胞，而且影响耳蜗微循环[40-43]。动物噪声暴露后血管通透性增加、血流量减少（局部缺血）、白细胞聚集及内皮细胞受损[44]。近期研究显示，首先声损伤后BLB结构和分子可发生改变，包括紧密连接蛋白和黏合连接蛋白表达量减少、内皮细胞间紧密连接缺失以及血管通透性增加[45-46]。其次，接触高强度声音后PCs易受到损伤。PCs呈不规则发育，可从ECs正常附着位置发生迁移，从而导致BLB失去稳定性[8]。再次，声损伤还可以激活一定比例PVM/ Ms，使其分泌色素上皮衍生因子（PEDF），导致紧密连接相关蛋白表达减少及血管渗透性增加[47]。由于PEDF控制紧密连接相关蛋白（如ZO-1和VE-cadherin）的表达，所以PVM/Ms分泌的PEDF对维持BLB的稳定性是必不可少的[4]。

3.2老年性聋

人颞骨研究中发现，老年性耳聋患者血管纹萎缩、BM增厚、免疫球蛋白增加以及层黏连蛋白沉积[48]。老年C57/6BJ小鼠[6]和基因缺陷NON⁃eH2nb1小鼠[49]中均发现血管纹毛细血管有一定程度的缺失。33月龄及以上的长爪沙鼠中65%-85%的血管纹毛细血管基膜增厚[50]。除此之外，还发现老年动物PCs和PVM/Ms分布密度明显降低，伴随血管纹明显的形态学改变[6]。例如，年轻C57/6BJ小鼠（<3个月）含有大量扁平、细长的PCs，且与ECs紧密相连。老年C57/6BJ小鼠（>6个月）PCs较少，胞体显著变圆，与ECs接触减少。有研究认为此形态学改变是PCs迁移征象[51]。超微结构显示，老年动物PCs细胞器减少，外观成液泡状，与ECs分离[6]。此外，老年动物中PVM/Ms也发生了变化。在年轻C57小鼠中PVM/Ms具有明显长足突，且与血管纹毛细血管紧密连接；然而在6、9和12个月龄的小鼠中，PVM/Ms足突变短；在21月龄小鼠中PVM/Ms为扁平状且似变形虫状，与毛细血管接触减少[6]。

3.3自身免疫性听力障碍

内耳自身免疫性疾病常常引起进行性感音神经性耳聋，有时表现为前庭症状（梅尼埃病）。攻击破坏血管纹毛细血管[52]。听力和前庭功能障碍都具有免疫复合物沉积和自身抗体直接破坏ECs的特点[52-53]。观察自身免疫鼠模型C3H/Ipr发现血管纹BLB完整性受损、毛细血管IgG沉积以及BM增厚。临床研究表明，自身免疫性听力障碍患者血液中抗内皮及抗磷脂抗体水平较高，包括胆碱转运蛋白样蛋白2和热休克蛋白（HSP70）[54]。导致血管纹BLB功能紊乱引起听力及前庭功能障碍。

3.4遗传性耳聋

在一些遗传性耳聋的病理学研究中发现BLB存在遗传缺陷，包括Norrie Disease、Alport syn⁃drome、Nr3b2（-/-）和Light（Blt）突变体、白斑（white spotting，Ws）和Varitint-waddler-J（VaJ）小鼠突变体，以及与耳聋相关的连接蛋白30缺失[37、55]。Nor⁃rie Disease主要因Ndp基因缺失导致血管纹中血管缺失引起重度感音神经性耳聋[56]。显性白斑小鼠有重度感音神经性耳聋突变体，使血管纹中间细胞缺失[57]。显性白斑病小鼠与老年性动物及自身免疫感音神经性聋动物的相同点是血管纹毛细血管BM增厚和IgG沉积。Light（Blt）突变体小鼠缺乏黑素细胞，导致血管纹萎缩、内淋巴电位缺失[58]。Al⁃port综合征由胶原蛋白α3、α4或α5基因突变导致血管纹毛细血管BM增厚引发高频感音神经性耳聋[55]。Nr3b2突变小鼠听力下降与血管纹毛细血管密度下降及连接蛋白30缺失破环BLB相关[37、59]。近期研究显示Spinster homolog2（Spns2）基因缺陷小鼠在2-3周龄时听力敏感性和内淋巴电位迅速下降。病理学提示血管纹毛细血管及边缘细胞边界结构发生明显改变[60]。

3.5炎症反应

有假设认为炎症因子诱导听力障碍与血管纹毛细血管完整性及内淋巴离子平衡紊乱相关[61]。近期研究表明脂多糖诱导的中耳炎因下调紧密连接蛋白表达而破坏耳蜗BLB[10]。且有实验验证脂多糖促进血清荧光素通过BLB进入外淋巴[38]。Quintanilla-Dieck2013年研究鼠类发现脂多糖引发的炎症可导致耳蜗细胞因子水平上调[62]。细胞因子水平的上调可能是BLB渗透率增加的原因之一。除炎症因子的作用外有研究表明，病毒或细菌感染引起抗内皮（抗磷脂）抗体攻击屏障上的多糖-蛋白质复合物[63]。综合这些研究表明全身或局部炎症可引起BLB功能紊乱，导致内稳态失衡及听力下降。

3.6血-迷路屏障为耳毒性药物的攻击靶点

耳毒性药物氨基糖苷类抗生素（如庆大霉素和阿米卡星），抗癌药（如顺铂、卡铂、奈达铂和奥沙利铂）以及循环利尿剂（如呋喃苯胺酸）具有损害人类和动物听觉和平衡感觉的副作用[40、64-66]。耳毒性药物可能通过BLB从血液进入内耳液体循环[67]。利尿剂或噪声暴露破坏BLB后可增加药物吸收率并且听力受损明显[68]。血管活性肽也可增加耳蜗对耳毒性药物的吸收，如庆大霉素[69]。血管纹药物吸收途径涉及转运系统及通路，包括血管纹毛细血管瞬时感受电位阳离子V 4通道（TRPV4）[70]。耳毒性药物可引起血管纹结构损伤，引发听力及平衡障碍。

4 总结

BLB包括ECs与大量紧密联系的辅助细胞（PPCs和PVM/Ms）和细胞外基膜蛋白，共同组成“耳蜗血管单位（cochlearvascular unit.）”。BLB对维持内耳电解质离子平衡以及防止有毒物质大量流入血管纹具有至关重要的作用。有观点认为，BLB的破坏与各种各样的临床听力障碍相关，包括自身免疫性内耳疾病、梅尼埃疾病、药物性耳聋、噪声性耳聋、突聋和遗传性耳聋。尽管BLB很重要，但是对其在听力和疾病中生理机能仍然知之甚少。目前相关知识的缺乏限制了BLB功能障碍相关性耳聋治疗的发展。对BLB的病理生理学更好的了解是研发新型医疗干预治疗BLB相关性耳聋和平衡失调所需要的基础。

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Advances in pathophysiologicalstudiesof cochlear blood-Labyrinth barrier

ZHANG Tong,HANWeiju
DepartmentofOtolaryngology Head and Neck Surgery,ChinesePLAGeneralHospital,Beijing,100853,China

HANWeiju Email:hanweiju@aliyun.com

The stria vascularis and spiral ligament are located in the lateralwall of the cochlea.The blood-labyrinth barrier(BLB)of the stria vascularis is awell-differentiated capillary network that regulates exchanges between the blood and interstitial fluid in the cochlea.This barrier protects the inner ear from toxic substances thatare produced by blood and selectively allows fluids,ionsand nutrients into the cochlea.The BLB plays an important role inmaintaining cochlear homeostasis.The BLB includes vascular endothelial cells(ECs),basementmembrane(BM),elaborated tight and adherens junctions,pericytes(PCs),and perivascular residentmacrophage-likemelanocytes(PVM/Ms).Interactionsbetween ECs,PVM/Ms and PCs,sim ilar to intercellular signaling,play a vital role in controlling vascular permeability and providing a suitable environment for hearing function.Breakdown of normal interactions between componentsof the BLB participates in genetic defects,inflammation,acoustic injury and aging.

C ochlea；Stria vascularis；Blood-labyrinth barrier；Hearing loss

R764

A

1672-2922（2017）02-257-6

2017-03-28审核人：翟所强）

10.3969/j.issn.1672-2922.2017.02.022

国家自然科学基金面上项目（No：81170908；81470683）

张桐，硕士研究生，研究方向:耳科学

韩维举，Email:hanweiju@aliyun.com