耳蝸血管紋血-迷路屏障病理生理學(xué)研究進(jìn)展

張桐 韓維舉

北京解放軍總醫(yī)院耳鼻咽喉頭頸外科（北京100853）

耳蝸血管紋血-迷路屏障病理生理學(xué)研究進(jìn)展

張桐 韓維舉

北京解放軍總醫(yī)院耳鼻咽喉頭頸外科（北京100853）

血管紋和螺旋韌帶位于耳蝸中階外側(cè)壁，其中血管紋的血-迷路屏障（blood-labyrinth barrier,BLB）是高度分化的毛細(xì)血管網(wǎng)，用于調(diào)控耳蝸血液和細(xì)胞間液的物質(zhì)交換。此屏障保護(hù)內(nèi)耳不接觸來(lái)自血液的有毒物質(zhì)，并且選擇性的透過(guò)離子、液體及營(yíng)養(yǎng)物質(zhì)至耳蝸。血-迷路屏障對(duì)維持耳蝸內(nèi)穩(wěn)態(tài)有重要的作用。血迷路屏障結(jié)構(gòu)上包括血管紋微血管內(nèi)皮細(xì)胞（endothelial cells,ECs）、周細(xì)胞（pericytes,PCs）、血管周?chē)奘杉?xì)胞樣黑色素細(xì)胞（perivascular residentmacrophage-likemelanocytes,PVM/Ms）、基膜（basementmembrance,BM）、復(fù)雜的緊密連接和黏合連接。ECs、PCs和PVM/Ms間的作用，類(lèi)似于細(xì)胞間信號(hào)傳導(dǎo)，對(duì)控制血管滲透性及為聽(tīng)功能提供適宜的環(huán)境起著至關(guān)重要的作用。在遺傳缺陷、炎癥、聲損傷以及衰老的病理?xiàng)l件下，血-迷路屏障各組份間正常的相互作用遭到破壞，進(jìn)而導(dǎo)致其通透性增加，引發(fā)聽(tīng)力障礙。

耳蝸；血管紋；血-迷路屏障；耳聾

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

Declaration of interest:Theauthors reportno conflictsof interest.

內(nèi)耳是一個(gè)非常穩(wěn)定的自體調(diào)節(jié)系統(tǒng)，通過(guò)血-迷路屏障（blood-labyrinth barrier,BLB）主動(dòng)或被動(dòng)轉(zhuǎn)運(yùn)離子、液體和營(yíng)養(yǎng)物來(lái)維持其平衡狀態(tài)[1-2]。正常功能的血管紋（指“血-迷路屏障”）對(duì)維持離子濃度和耳蝸內(nèi)電位（EP）穩(wěn)定有重要的作用[3-5]。血管紋BLB功能障礙是自身免疫性?xún)?nèi)耳疾病、噪聲性聾、老年性聾和遺傳性聾的原因之一[6-10]。本文綜述血管紋BLB的病理生理學(xué)研究進(jìn)展。

1 耳蝸血-迷路屏障的主要成分及結(jié)構(gòu)

血管紋外接螺旋韌帶位于耳蝸中階外側(cè)壁，主要包括基底細(xì)胞（basal cell,BC）、中間細(xì)胞（inter?mediate cell,IC）和邊緣細(xì)胞（marginal cell,MC）[11]。BLB是一個(gè)特殊分化的毛細(xì)血管網(wǎng)，位于血管紋中間層。其結(jié)構(gòu)包括內(nèi)皮細(xì)胞（endothelial cells, ECs）、基膜（basementmembrane,BM）、周細(xì)胞（peri?cytes,PCs）[12]及血管周?chē)奘杉?xì)胞樣黑色素細(xì)胞（perivascular residentmacrophage-like melanocytes, PVM/Ms）[13]。BLB通過(guò)緊密連接、膜屏障和化學(xué)作用控制離子、液體和營(yíng)養(yǎng)物從血液循環(huán)進(jìn)入血管紋[7、14]。

正常成年C57/6J小鼠耳蝸血-迷路屏障內(nèi)存在約1220-1300個(gè)周細(xì)胞（PCs），形態(tài)上有很多足突，緊貼在血管紋毛細(xì)血管壁，嵌入到基膜內(nèi)[6]。血管紋PCs表達(dá)血小板源內(nèi)皮生長(zhǎng)因子受體β（plate?let-derived growth factor receptor-β,PDGFR-β）、結(jié)蛋白（desmin）、神經(jīng)/膠質(zhì)抗原2（neural/glial anti?gen2,NG2）和CD90（胸腺抗原-1，Thy-1）[12]。血管紋PCs含有豐富的結(jié)蛋白，屬于一種中間纖維蛋白質(zhì)，可增強(qiáng)細(xì)胞構(gòu)架機(jī)械強(qiáng)度且提高血管網(wǎng)物理彈性[12]。螺旋韌帶PCs則更多表達(dá)收縮蛋白，如平滑肌肌動(dòng)蛋白（α-SMA）和原肌球蛋白[12、15]。目前研究發(fā)現(xiàn)，PCs對(duì)血管生成、血流調(diào)節(jié)、血管完整性和組織纖維增生有重要作用[16]。PCs通過(guò)調(diào)節(jié)ECs間緊密連接蛋白的表達(dá)調(diào)控BLB的完整性[17]。體外細(xì)胞系3D共同培養(yǎng)實(shí)驗(yàn)研究發(fā)現(xiàn)PCs具有明顯促進(jìn)血管新生的作用[6]。非耳蝸組織中，PCs通過(guò)直接合成膠原蛋白IV(collagenIV)、粘多糖、纖維蛋白、巢蛋白-1、基底膜聚糖（串珠素，蛋白多糖）和層連粘蛋白促進(jìn)基膜的形成[18]；抑制不穩(wěn)定基質(zhì)金屬蛋白酶(MMP)的活性，如MMP-2和MMP-9[19-20]。正常成年C57/6J小鼠耳蝸的血-迷路屏障內(nèi)存在一定數(shù)量的血管周?chē)ｑv巨噬樣色素細(xì)胞(PVM/ Ms)[21]。多數(shù)觀點(diǎn)認(rèn)為PVM/Ms起源于耳蝸神經(jīng)嵴黑色素細(xì)胞，隨著發(fā)育遷移至耳蝸血管紋[22]。PVM/ Ms的位置極為貼近邊緣細(xì)胞層下方，且多個(gè)足突與毛細(xì)血管管腔表面緊密接觸。PVM/Ms是一種混合型細(xì)胞，具有巨噬細(xì)胞和黑色素細(xì)胞的特性[4]。早期研究發(fā)現(xiàn)，血管紋PVM/Ms表達(dá)一系列巨噬細(xì)胞表面抗原，包括F4/80、CD68和CD11b[13]。近期研究發(fā)現(xiàn)，PVM/Ms還具有黑素細(xì)胞的特性，包括含有大量的黑色素和表達(dá)黑素細(xì)胞標(biāo)記蛋白，例如谷胱甘肽S-轉(zhuǎn)移酶α4（Gatα4）和Kir4.1，后者為中間細(xì)胞的標(biāo)記蛋白[4]。

ECs和PVM/Ms間的物理連接和信號(hào)傳導(dǎo)調(diào)控BLB的完整性及穩(wěn)定性[4]。PVM/Ms具有黑色素細(xì)胞的特性，為抵抗有害因素在局部組織生成黑色素[23]。黑色素通過(guò)緩沖鈣，清除重金屬、外源蛋白質(zhì)及脂質(zhì)，促進(jìn)抗氧化活性而維持組織穩(wěn)態(tài)[24]。血管紋PVM/Ms具有免疫防御及修復(fù)功能，例如：清除入侵的微生物及壞死細(xì)胞；PVM/Ms可作為免疫、炎性效應(yīng)細(xì)胞產(chǎn)生超氧化物陰離子、一氧化氮和炎性因子[25-27]。一些研究認(rèn)為，其他器官組織的固有巨噬細(xì)胞在組織受損修復(fù)時(shí)能夠分化為成纖維細(xì)胞/成肌纖維細(xì)胞[28]。

BLB內(nèi)基膜（BM）除主要包括膠原蛋白IV、層粘連蛋白、硫酸乙酰肝素蛋白多糖（HSPG）、巢蛋白和纖連蛋白外，還發(fā)現(xiàn)有β1和α1整合蛋白亞基[29-30]。BM中不同蛋白質(zhì)相互作用形成均勻的致密板[31]。超微結(jié)構(gòu)顯示基膜蛋白聚糖呈多樣化及模式化分布，且血管紋基膜帶負(fù)電荷[32]。

2 血-迷路屏障的滲透性

動(dòng)物實(shí)驗(yàn)發(fā)現(xiàn)幼年動(dòng)物較成年動(dòng)物的血管紋BLB滲透性更強(qiáng)。例如，Suzuki曾報(bào)道大鼠14日齡前其血管紋BLB未完全形成[33]。

主要通過(guò)細(xì)胞外和跨細(xì)胞兩種途徑控制血管紋BLB通透性。細(xì)胞外途徑與內(nèi)皮細(xì)胞間緊密連接蛋白瞬時(shí)狀態(tài)相關(guān)?？缂?xì)胞途徑包含吞飲和跨內(nèi)皮渠道。BLB主要連接蛋白包括緊密連接蛋白o(hù)ccludin、claudins、zona occludens和黏合連接蛋白如鈣粘素（VE-cadherin）[9、34]。近期實(shí)驗(yàn)表明緊密連接蛋白和黏合連接蛋白表達(dá)上調(diào)可提高屏障的完整性[4]。相反的，緊密連接蛋白和黏合連接蛋白表達(dá)下調(diào)可增加屏障的滲透性[4、34]。另外，跨細(xì)胞途徑滲透率依賴(lài)于轉(zhuǎn)運(yùn)蛋白及轉(zhuǎn)運(yùn)通道。BLB中富含轉(zhuǎn)運(yùn)蛋白。例如，離體血管紋微血管質(zhì)譜分析提示BLB中40%蛋白與轉(zhuǎn)運(yùn)蛋白相關(guān)[9]。

3 血-迷路屏障與聽(tīng)力障礙

BLB功能紊亂可導(dǎo)致聽(tīng)力出現(xiàn)障礙，如噪聲性耳聾[35]、老年性耳聾[6]、自身免疫性疾病[36]、遺傳性聽(tīng)力障礙[37]和炎性水腫[38]。此外，耳毒性藥物也可通過(guò)BLB進(jìn)入內(nèi)耳，破壞聽(tīng)力功能。如順鉑類(lèi)和氨基糖苷類(lèi)藥物[39]。盡管這些病理?xiàng)l件使BLB通透性和選擇性發(fā)生改變，但是他們?nèi)愿髯跃哂歇?dú)特的特性。

3.1噪聲性聽(tīng)力損傷（NIHL）

聲損傷不但破壞感覺(jué)毛細(xì)胞、神經(jīng)細(xì)胞和支持細(xì)胞，而且影響耳蝸微循環(huán)[40-43]。動(dòng)物噪聲暴露后血管通透性增加、血流量減少（局部缺血）、白細(xì)胞聚集及內(nèi)皮細(xì)胞受損[44]。近期研究顯示，首先聲損傷后BLB結(jié)構(gòu)和分子可發(fā)生改變，包括緊密連接蛋白和黏合連接蛋白表達(dá)量減少、內(nèi)皮細(xì)胞間緊密連接缺失以及血管通透性增加[45-46]。其次，接觸高強(qiáng)度聲音后PCs易受到損傷。PCs呈不規(guī)則發(fā)育，可從ECs正常附著位置發(fā)生遷移，從而導(dǎo)致BLB失去穩(wěn)定性[8]。再次，聲損傷還可以激活一定比例PVM/ Ms，使其分泌色素上皮衍生因子（PEDF），導(dǎo)致緊密連接相關(guān)蛋白表達(dá)減少及血管滲透性增加[47]。由于PEDF控制緊密連接相關(guān)蛋白（如ZO-1和VE-cadherin）的表達(dá)，所以PVM/Ms分泌的PEDF對(duì)維持BLB的穩(wěn)定性是必不可少的[4]。

3.2老年性聾

人顳骨研究中發(fā)現(xiàn)，老年性耳聾患者血管紋萎縮、BM增厚、免疫球蛋白增加以及層黏連蛋白沉積[48]。老年C57/6BJ小鼠[6]和基因缺陷NON?eH2nb1小鼠[49]中均發(fā)現(xiàn)血管紋毛細(xì)血管有一定程度的缺失。33月齡及以上的長(zhǎng)爪沙鼠中65%-85%的血管紋毛細(xì)血管基膜增厚[50]。除此之外，還發(fā)現(xiàn)老年動(dòng)物PCs和PVM/Ms分布密度明顯降低，伴隨血管紋明顯的形態(tài)學(xué)改變[6]。例如，年輕C57/6BJ小鼠（<3個(gè)月）含有大量扁平、細(xì)長(zhǎng)的PCs，且與ECs緊密相連。老年C57/6BJ小鼠（>6個(gè)月）PCs較少，胞體顯著變圓，與ECs接觸減少。有研究認(rèn)為此形態(tài)學(xué)改變是PCs遷移征象[51]。超微結(jié)構(gòu)顯示，老年動(dòng)物PCs細(xì)胞器減少，外觀成液泡狀，與ECs分離[6]。此外，老年動(dòng)物中PVM/Ms也發(fā)生了變化。在年輕C57小鼠中PVM/Ms具有明顯長(zhǎng)足突，且與血管紋毛細(xì)血管緊密連接；然而在6、9和12個(gè)月齡的小鼠中，PVM/Ms足突變短；在21月齡小鼠中PVM/Ms為扁平狀且似變形蟲(chóng)狀，與毛細(xì)血管接觸減少[6]。

3.3自身免疫性聽(tīng)力障礙

內(nèi)耳自身免疫性疾病常常引起進(jìn)行性感音神經(jīng)性耳聾，有時(shí)表現(xiàn)為前庭癥狀（梅尼埃?。?。攻擊破壞血管紋毛細(xì)血管[52]。聽(tīng)力和前庭功能障礙都具有免疫復(fù)合物沉積和自身抗體直接破壞ECs的特點(diǎn)[52-53]。觀察自身免疫鼠模型C3H/Ipr發(fā)現(xiàn)血管紋BLB完整性受損、毛細(xì)血管IgG沉積以及BM增厚。臨床研究表明，自身免疫性聽(tīng)力障礙患者血液中抗內(nèi)皮及抗磷脂抗體水平較高，包括膽堿轉(zhuǎn)運(yùn)蛋白樣蛋白2和熱休克蛋白（HSP70）[54]。導(dǎo)致血管紋BLB功能紊亂引起聽(tīng)力及前庭功能障礙。

3.4遺傳性耳聾

在一些遺傳性耳聾的病理學(xué)研究中發(fā)現(xiàn)BLB存在遺傳缺陷，包括Norrie Disease、Alport syn?drome、Nr3b2（-/-）和Light（Blt）突變體、白斑（white spotting，Ws）和Varitint-waddler-J（VaJ）小鼠突變體，以及與耳聾相關(guān)的連接蛋白30缺失[37、55]。Nor?rie Disease主要因Ndp基因缺失導(dǎo)致血管紋中血管缺失引起重度感音神經(jīng)性耳聾[56]。顯性白斑小鼠有重度感音神經(jīng)性耳聾突變體，使血管紋中間細(xì)胞缺失[57]。顯性白斑病小鼠與老年性動(dòng)物及自身免疫感音神經(jīng)性聾動(dòng)物的相同點(diǎn)是血管紋毛細(xì)血管BM增厚和IgG沉積。Light（Blt）突變體小鼠缺乏黑素細(xì)胞，導(dǎo)致血管紋萎縮、內(nèi)淋巴電位缺失[58]。Al?port綜合征由膠原蛋白α3、α4或α5基因突變導(dǎo)致血管紋毛細(xì)血管BM增厚引發(fā)高頻感音神經(jīng)性耳聾[55]。Nr3b2突變小鼠聽(tīng)力下降與血管紋毛細(xì)血管密度下降及連接蛋白30缺失破環(huán)BLB相關(guān)[37、59]。近期研究顯示Spinster homolog2（Spns2）基因缺陷小鼠在2-3周齡時(shí)聽(tīng)力敏感性和內(nèi)淋巴電位迅速下降。病理學(xué)提示血管紋毛細(xì)血管及邊緣細(xì)胞邊界結(jié)構(gòu)發(fā)生明顯改變[60]。

3.5炎癥反應(yīng)

有假設(shè)認(rèn)為炎癥因子誘導(dǎo)聽(tīng)力障礙與血管紋毛細(xì)血管完整性及內(nèi)淋巴離子平衡紊亂相關(guān)[61]。近期研究表明脂多糖誘導(dǎo)的中耳炎因下調(diào)緊密連接蛋白表達(dá)而破壞耳蝸BLB[10]。且有實(shí)驗(yàn)驗(yàn)證脂多糖促進(jìn)血清熒光素通過(guò)BLB進(jìn)入外淋巴[38]。Quintanilla-Dieck2013年研究鼠類(lèi)發(fā)現(xiàn)脂多糖引發(fā)的炎癥可導(dǎo)致耳蝸細(xì)胞因子水平上調(diào)[62]。細(xì)胞因子水平的上調(diào)可能是BLB滲透率增加的原因之一。除炎癥因子的作用外有研究表明，病毒或細(xì)菌感染引起抗內(nèi)皮（抗磷脂）抗體攻擊屏障上的多糖-蛋白質(zhì)復(fù)合物[63]。綜合這些研究表明全身或局部炎癥可引起B(yǎng)LB功能紊亂，導(dǎo)致內(nèi)穩(wěn)態(tài)失衡及聽(tīng)力下降。

3.6血-迷路屏障為耳毒性藥物的攻擊靶點(diǎn)

耳毒性藥物氨基糖苷類(lèi)抗生素（如慶大霉素和阿米卡星），抗癌藥（如順鉑、卡鉑、奈達(dá)鉑和奧沙利鉑）以及循環(huán)利尿劑（如呋喃苯胺酸）具有損害人類(lèi)和動(dòng)物聽(tīng)覺(jué)和平衡感覺(jué)的副作用[40、64-66]。耳毒性藥物可能通過(guò)BLB從血液進(jìn)入內(nèi)耳液體循環(huán)[67]。利尿劑或噪聲暴露破壞BLB后可增加藥物吸收率并且聽(tīng)力受損明顯[68]。血管活性肽也可增加耳蝸對(duì)耳毒性藥物的吸收，如慶大霉素[69]。血管紋藥物吸收途徑涉及轉(zhuǎn)運(yùn)系統(tǒng)及通路，包括血管紋毛細(xì)血管瞬時(shí)感受電位陽(yáng)離子V 4通道（TRPV4）[70]。耳毒性藥物可引起血管紋結(jié)構(gòu)損傷，引發(fā)聽(tīng)力及平衡障礙。

4 總結(jié)

BLB包括ECs與大量緊密聯(lián)系的輔助細(xì)胞（PPCs和PVM/Ms）和細(xì)胞外基膜蛋白，共同組成“耳蝸血管單位（cochlearvascular unit.）”。BLB對(duì)維持內(nèi)耳電解質(zhì)離子平衡以及防止有毒物質(zhì)大量流入血管紋具有至關(guān)重要的作用。有觀點(diǎn)認(rèn)為，BLB的破壞與各種各樣的臨床聽(tīng)力障礙相關(guān)，包括自身免疫性?xún)?nèi)耳疾病、梅尼埃疾病、藥物性耳聾、噪聲性耳聾、突聾和遺傳性耳聾。盡管BLB很重要，但是對(duì)其在聽(tīng)力和疾病中生理機(jī)能仍然知之甚少。目前相關(guān)知識(shí)的缺乏限制了BLB功能障礙相關(guān)性耳聾治療的發(fā)展。對(duì)BLB的病理生理學(xué)更好的了解是研發(fā)新型醫(yī)療干預(yù)治療BLB相關(guān)性耳聾和平衡失調(diào)所需要的基礎(chǔ)。

1 Juhn SK,Rybak LP.Labyrinthine Barriers and Cochlear Homeo?stasis[J].Acta Oto-laryngologica,1981,91(5-6):529-534.

2 Juhn SK,Hunter BA,Odland RM.Blood-labyrinth Barrier and Fluid Dynamics of The Inner Ear[J].The International Tinnitus Journal,2001,7(2):72-83.

3 Hibino H,Nin F,TsuzukiC,etal.How is The Highly Positive En?docochlear Potential Formed?The Specific Architecture of The Stria Vascularis and The Roles of The Ion-transport Apparatus [J].Pflugers Archiv:European Journal of Physiology,2010,459 (4):521-533.

4 ZhangW,DaiM,Fridberger A,et al.Perivascular-residentMac?rophage-like Melanocytes in The Inner Ear are Essential for The Integrity of The Intrastrial Fluid-blood Barrier[J].Proceedings of the National Academy of Sciences of the United States of Ameri?ca,2012,109(26):10388-10393.

5吳軍,韓維舉.耳蝸血-迷路屏障與噪聲性聽(tīng)力損傷[J].聽(tīng)力學(xué)及言語(yǔ)疾病雜志,2015,23(04):427-430.

Wu J,Han WJ.Cochlear Blood-labrinth Barrier and Noise-in?duced Hearing loss[J].Journal of Audiology and Speech Patholo?gy,2015,23(04):427-430.

6 Neng L,Zhang J,Yang J,et al.Structural Changes in Thestrial Blood-labyrinth Barrier of Aged C57BL/6 mice[J].Cell and Tis?sue Research,2015,361(3):685-696.

7許慶慶,郭維維,翟所強(qiáng),等.耳蝸血管紋細(xì)胞離子轉(zhuǎn)運(yùn)的研究進(jìn)展[J].中華耳科學(xué)雜志,2015,13(01):30-36.

Xu QQ,GuoWW,Zhai SQ,et al.A Review of Research on Ionic Transportin Cochlear Stria Vascularis[J].Chinese JournalofOtol?ogy,2015,13(01):30-36.

8 SHIX.Cochlear Pericyte Responses to Acoustic Trauma and The Involvement of Hypoxia-inducible Factor-1alpha and Vascular Endothelial Growth Factor[J].The American Journal of Patholo?gy,2009,174(5):1692-1704.

9 Yang Y,DaiM,Wilson TM,etal.Na+/K+-ATPase Alpha1 Identi?fied as An Abundant Protein in The Blood-labyrinth Barrier That Plays An Essential Role in The Barrier Integrity[J].PloSOne, 2011,6(1):1931-6203.

10 Zhang J,ChenS,Hou Z,et al.Lipopolysaccharide-induced Mid?dle Ear Inflammation Disrupts The Cochlear Intra-strial Flu?id-Blood Barrier Through Down-Regulation of Tight Junction Pro?teins[J].PloSOne,2015,10(3):1932-6203.

11侯赟,郭維維,楊仕明,等.耳蝸血管紋的發(fā)育及異常所導(dǎo)致的耳聾疾病[J].中華耳科學(xué)雜志,2012,10(04):528-532.

Hou Y,GuoWW,Yang SM,et al.Occurrence of Cochlear Vascular Lines and Abnormalities Caused by Deafness[J].Chinese Jour?nalofOtology,2012,10(04):528-532.

12 Shi X,Han W,Yamammoto H,et al.The Cochlear Pericytes[J]. Microcirculation(New York,NY:1994),2008,15(6):515-529.

13 Shi X.Resident Macrophages In The Cochlear Blood-labyrinth Barrier and Their Renewal Via Migration of Bone-marrow-de?rived Cells[J].Celland Tissue Research,2010,342(1):21-30.

14胡博華.噪聲性耳聾:基礎(chǔ)研究進(jìn)展和展望[J].中華耳科學(xué)雜志,2016,14(06):693-700.

Hu BH.Noise Deafness:Basic Research Progress and Prospect [J].Chinese JournalofOtology,2016,14(06):693-700.

15 Franz P,Helm relch M,Stach M,et al.Distribution of Actin and Myosin in The Cochlear Microvascular Bed[J].Acta Oto-laryngo?logica,2004,124(4):481-485.

16 HallCN,reynellC,Gesslein B,etal.Capillary Pericytes Regulate Cerebral Blood Flow in Health and Disease[J].Nature,2014,508 (7494):55-60.

17 Neng L,Zhang F,Kachelmeier A,et al.Endothelial Cell,Peri?cyte,and Perivascular ResidentMacrophage-type Melanocyte In?teractions Regulate Cochlear Intrastrial Fluid-blood Barrier Per?meability[j].Journalof The Association for Research in Otolaryn?gology:JARO,2013,14(2):175-85.

18 Allt G,Lawrenson JG.Pericytes:Cell Biology And Pathology[J]. Cells,Tissues,Organs,2001,169(1):1-11.

19吳軍.噪聲引起的血管紋基質(zhì)金屬蛋白酶變化及其對(duì)耳蝸血—迷路屏障的影響[D];中國(guó)人民解放軍醫(yī)學(xué)院,2014.

Wu J.Noise Induced Matrix Metalloproteinases Changes and Its Effect on Blood-labyrinth Barrier[D];Chinese PLA General Hos?pital,2014.

20 Zozulya A,Weidenfeller C,galla HJ.Pericyte-endothelialCell In?teraction Increases MMP-9 Secretion at The Blood-Brain Barrier in Vitro[J].Brain Research,2008,(1189):1-11.

21 Shi X.Pathophysiology of The Cochlear Intrastrial Fluid-Blood Barrier(Review)[J].Hearing Research,2016,(338):52-63.

22 Wakaoka T,Motohashi T,Hayashi H,et al.Tracing Sox10-ex?pressing Cells Elucidates The Dynamic Development of The Mouse Inner Ear[J].Hearing Research,2013,(302):17-25.

23 Soulas C,Donahue RE,Dunbar CE,et al.Genetically Modified CD34+Hematopoietic Stem Cells Contribute to Turnover of Brain Perivascular Macrophages in Long-term Repopulated Primates[J].The American Journalof Pathology,2009,174(5):1808-1817.

24 Slominski A,Zmijewski MA,Pawelek J.L-tyrosine and L-dihy?droxyphenylalanine as Hormone-Like Regulators of Melanocyte Functions[J].Pigment Cell&Melanoma Research,2012,25(1): 14-27.

25 Cui Q,Yin Y,Benowitz L I.The Role of Macrophages in Optic Nerve Regeneration[J].Neuroscience,2009,158(3):1039-1048.

26 Mitrasinovic OM,Grattan A,Robinson CC,etal.Microglia Over?expressing The Macrophage Colony-Stimulating Factor Receptor are Neuroprotective in a Microglial-hippocampal Organotypic Co?culture System[J].The Journal of Neuroscience:The Official Journal of The Society for Neuroscience,2005,25(17): 4442-4451.

27 Nimmerjahn A,Kirchhoff F,Helmchen F.Resting Microglial Cellsare Highly Dynamic Surveillantsof Brain Parenchyma in Vi?vo[J].Science(New York,NY),2005,308(5726):1314-1318.

28 Pilling D,Fan T,Huang D,et al.Identification of Markers that Distinguish Monocyte-Derived Fibrocytes From Monocytes,Mac?rophages,and Fibroblasts[J].PloSOne,2009,4(10):74-75.

29 Gratton MA,Meehan DT,Smyth BJ,et al.Strial Marginal Cells Play A Role in BasementMembrane Homeostasis:in Vitro and in Vivo Evidence[J].Hearing Research,2002,163(1-2):27-36.

30 Bhattacharya G,Miller C,KimberlingWJ,et al.Localization and Expression of Usherin:a Novel Basement Membrane Protein De?fective in PeopleWith Usher's Syndrome Type Iia[J].Hearing Re?search,2002,163(1-2):1-11.

31 Tsuprun V,Santi P.Proteoglycan Arrays in The Cochlear Base?mentMembrane[J].Hearing Research,2001,157(1-2):65-76.

32 Suzuki M,Kaga K.Effect of Cisplatin on The Negative Charge Barrier in Strial Vessels of The Guinea Pig.A Transmission Elec?tron Microscopic Study Using Polyethyleneimine Molecules[J]. European Archives of Oto-rhino-laryngology:Official Journal of The European Federation of Oto-rhino-laryngological Societies (EUFOS):Affiliated with The German Society for Oto-rhino-lar?yngology-head and Neck Surgery,1996,253(6):351-355.

33 SuzukiM,Yamasoba T,KAGA K.Developmentof The Blood-lab?yrinth Barrier in The Rat[J].Hearing Research,1998,116(1-2): 107-112.

34 Neng L,ZhangW,Hassan A,etal.Isolation and Culture of Endo?thelial Cells,Pericytes and Perivascular Resident Macro?phage-like Melanocytes from The Young Mouse Ear[J].Nature protocols,2013,8(4):709-720.

35 Shi X,Nuttall AL.Upregulated iNOS and Oxidative Damage to The Cochlear Stria Vascularis Due to Noise Stress[J].Brain Re?search,2003,967(1-2):1-10.

36 Ruckenstein MJ,Hul.Antibody Deposition in The Stria Vascu?larisof The MRL-fas(lpr)Mouse[J].Hearing Research,1999,127 (1-2):137-142.

37 Cohen-Salmon M,Regnault B,CAYETN,etal.Connexin30 Defi?ciency Causes Instrastrial Fluid-blood Barrier Disruption within The Cochlear Stria Vascularis[J].Proceedings of the National Academy of Sciences of the United States of America,2007,104 (15):6229-6234.

38 Hirose K,Hartsock JJ,Johnson S,etal.Systemic Lipopolysaccha?ride Compromises The Blood-labyrinth Barrier and Increases En?try of Serum Fluorescein into The Perilymph[J].Journal of The Association for Research in Otolaryngology:JARO,2014,15(5): 707-719.

39 Wang Q,Steyger PS.Trafficking of Systemic FluorescentGentami? cin into The Cochlea and Hair Cells[J].Journal of The Associa?tion for Research in Otolaryngology:JARO,2009,10(2): 205-219.

40 Kamogashira T,Fujimoto C,Yamasoba T.Reactive Oxygen Spe?cies,Apoptosis,and Mitochondrial Dysfunction in Hearing Loss [J].2015,15(6):17-20.

41 Kujawa SG,Liberman MC.Synaptopathy in The Noise-exposed and Aging Cochlea:Primary Neural Degeneration in Acquired Sensorineural Hearing Loss[J].Hearing Research,2015,330(Pt B):191-199.

42 Liberman LD,Suzuki J,Liberman MC.Erratum to:Dynamics of Cochlear Synaptopathy After Acoustic Overexposure[J].Journal of The Association for Research in Otolaryngology:JARO,2015, 16(2):221.

43朱恒濤,管俐娜,江紅群.噪聲性耳聾病理機(jī)制的研究進(jìn)展[J].中華耳科學(xué)雜志,2016,14(05):681-685.

Zhu HT,Guan LN,Jiang HQ.PathologicalMechanismsof Noise-in?duced Hearing Loss：A review of Recent Research[J].Chi?nese JournalofOtology,2016,14(05):681-685.

44 Shi X,Nuttall AL.Expression of Adhesion Molecular Proteins in The Cochlear LateralWall of Normal and PARP-1 Mutant Mice [J].Hearing Research,2007,224(1-2):1-14.

45 Zhang F,DaiM,Neng L,etal.PerivascularMacrophage-likeMe?lanocyte Responsiveness to Acoustic Trauma--a Salient Feature of Strial Barrier Associated Hearing Loss[J].FASEB journal:Of?ficial Publication of The Federation of American Societies for Ex?perimentalBiology,2013,27(9):3730-40.

46吳永翔,朱國(guó)霞,劉新秦,等.噪聲對(duì)豚鼠耳蝸血管紋緊密連接蛋白Claudin-5表達(dá)及血迷路屏障通透性的影響[J].聽(tīng)力學(xué)及言語(yǔ)疾病雜志,2012,20(02):145-150.

Wu YX,Zhu GX,LiuU XT,etal.Effects of Noise on Claudin-5 Ex?pression and Permeability of Blood Labyrinth Barrier in Cochlear Vascular Cochlea of Guinea Pigs[J].Journal of Audiology and Speech Pathology,2012,20(02):145-150.

47張文靜.小鼠內(nèi)耳外周常駐巨噬細(xì)胞樣黑色素細(xì)胞在血迷路屏障中的重要作用[D];鄭州大學(xué),2014.

Zhang WJ.Perivascular-resident Macrophage-like Melanocytes in The Inner Ear are Essential for The Integrity of The Intrastrial Fluid-blood Barrier[D];Zhengzhou University,2014.

48 Sprinzl GM,Riechelmann H.Current Trends in Treating Hearing Loss in Elderly People:a Review of The Technology and Treat?ment Options-a mini-review[J].Gerontology,2010,56(3): 351-358.

49 Ohlemiller KK,Rice ME,Gagnon PM.Strial Microvascular Pa?thology and Age-Associated Endocochlear Potential Decline in NOD Congenic Mice[J].Hearing Research,2008,244(1-2): 85-97.

50 Thomopoulos GN,SPICER SS,GRATTONM A,etal.Age-relat?ed Thickening of Basement Membrane in Stria Vascularis Capil?laries[J].Hearing Research,1997,111(1-2):31-41.

51 Pfister F,Feng Y,Vom HF,et al.Pericyte Migration:A Novel Mechanism of Pericyte Loss in Experimental Diabetic Retinopa?thy[J].Diabetes,2008,57(9):2495-2502.

52 Goodall AF,Siddiq MA.CurrentUnderstanding of The Pathogene?sis of Autoimmune Inner Ear Disease:A Review[J].ClinicalOto?laryngology:Official Journal of ENT-UK;Official Journal of Netherlands Society for Oto-rhino-laryngology&Cervico-facial Surgery,2015,40(5):412-419.

53 Agruf C,Luxonl M.Immune-mediated Inner-ear Disorders inNeuro-otology[J].Current Opinion in Neurology,2006,19(1): 26-32.

54 Mijovic T,Zeitouni A,Colmegna I.Autoimmune Sensorineural Hearing Loss:The Otology-rheumatology Interface[J].Rheumatol?ogy(Oxford,England),2013,52(5):780-789.

55 ZallocchiM,Johnson BM,Meehan DT,et al.Alpha1beta1 Integ?rin/Rac1-dependent Mesangial Invasion of Glomerular Capillar?ies in Alport Syndrome[J].The American Journal of Pathology, 2013,183(4):1269-1280.

56 Rehm HL,Zhang DS,Brown MC,etal.Vascular Defectsand Sen?sorineural Deafness in a Mouse Model of Norrie Disease[J].The Journal of Neuroscience:The Official Journal of the Society for Neuroscience,2002,22(11):4286-4292.

57 Fujimura T,Suzuki H,Shimizu T,et al.Pathological Alterations of Strial Capillaries in DominantWhite Spotting W/Wv mice[J]. Hearing Research,2005,209(1-2):53-59.

58 Cable J,Jackson IJ,Steel KP.Light(Blt),A Mutation that Causes Melanocyte Death,Affects Stria Vascularis Function in The Mouse Inner Ear[J].Pigment Cell Research,1993,6(4 Pt 1): 215-225.

59 Chen J,Nathans J.Estrogen-related Receptor Beta/NR3B2 Con?trols Epithelial Cell Fate and Endolymph Production by The Stria Vascularis[J].DevelopmentalCell,2007,13(3):325-337.

60 Chen J,Ingham N,Kelly J,etal.Spinster Homolog 2(Spns2)Defi?ciency Causes Early OnsetProgressive Hearing Loss[J].PLoSGe?netics,2014,10(10):46-48.

61 Trune DR,Nguyen-huynh A.Vascular Pathophysiology in Hear?ing Disorders[J].Seminars in Hearing,2012,33(3):242-250.

62 Quintanilla-dieck L,Larrain B,Trune D,et al.Effect of Systemic Lipopolysaccharide-induced Inflammation on Cytokine Levels in The Murine Cochlea:A Pilot Study[J].Otolaryngology--head and Neck Surgery:Official Journal of American Academy of Otolaryn?gology-Head and Neck Surgery,2013,149(2):301-303.

63 Blank M,Barzilai O,Shoenfeld Y.Molecular Mimicry and Au?to-immunity[J].Clinical Reviews in Allergy&Immunology, 2007,32(1):111-118.

64 Ding D,Allman BL,Salvi R.Review:Ototoxic Characteristics of Platinum Antitumor Drugs[J].Anatomical Record(Hoboken,NJ: (2007),2012,295(11):1851-1867.

65 Oishi N,Talaska AE,Schacht J.Ototoxicity in Dogs and Cats[J]. The Veterinary Clinics of North America Small Animal Practice, 2012,42(6):1259-1271.

66 Schacht J,Talaska AE,Rybak LP.Cisplatin and Aminoglycoside Antibiotics:Hearing Loss and Its Prevention[J].Anatomical Re?cord(Hoboken,NJ:2007),2012,295(11):1837-1850.

67 Adamson R.Role of Macrophages in NormalWound Healing:An Overview[J].JournalofWound Care,2009,18(8):349-351.

68 Li H,Kachelmeier A,Furness DN,et al.Local Mechanisms for Loud Sound-enhanced Aminoglycoside Entry into Outer Hair Cells[J].Frontiers in Cellular Neuroscience,2015,9(6):130.

69 Koo JW,Wang Q,Steyger PS.Infection-mediated Vasoactive Pep?tides Modulate Cochlear Uptake of Fluorescent Gentamicin[J]. Audiology&Neuro-otology,2011,16(6):347-358.

70 Ishibashi T,Takumida M,Akagi N,et al.Changes in Transient Receptor Potential Vanilloid(TRPV)1,2,3 and 4 Expressionin Mouse Inner Ear Following Gentamicin Challenge[J].Acta oto-laryngologica,2009,129(2):116-126.

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審核人：翟所強(qiáng)）

10.3969/j.issn.1672-2922.2017.02.022

國(guó)家自然科學(xué)基金面上項(xiàng)目（No：81170908；81470683）

張桐，碩士研究生，研究方向:耳科學(xué)

韓維舉，Email:hanweiju@aliyun.com