耳蝸血管紋血-迷路屏障病理生理學研究進展

張桐 韓維舉

北京解放軍總醫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研究進展

張桐 韓維舉

北京解放軍總醫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壁，其中血管紋的血-迷路屏障（blood-labyrinth barrier,BLB）是高度分化的毛細血管網，用于調控耳蝸血液和細胞間液的物質交換。此屏障保護內耳不接觸來自血液的有毒物質，并且選擇性的透過離子、液體及營養物質至耳蝸。血-迷路屏障對維持耳蝸內穩態有重要的作用。血迷路屏障結構上包括血管紋微血管內皮細胞（endothelial cells,ECs）、周細胞（pericytes,PCs）、血管周圍巨噬細胞樣黑色素細胞（perivascular residentmacrophage-likemelanocytes,PVM/Ms）、基膜（basementmembrance,BM）、復雜的緊密連接和黏合連接。ECs、PCs和PVM/Ms間的作用，類似于細胞間信號傳導，對控制血管滲透性及為聽功能提供適宜的環境起著至關重要的作用。在遺傳缺陷、炎癥、聲損傷以及衰老的病理條件下，血-迷路屏障各組份間正常的相互作用遭到破壞，進而導致其通透性增加，引發聽力障礙。

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.

內耳是一個非常穩定的自體調節系統，通過血-迷路屏障（blood-labyrinth barrier,BLB）主動或被動轉運離子、液體和營養物來維持其平衡狀態[1-2]。正常功能的血管紋（指“血-迷路屏障”）對維持離子濃度和耳蝸內電位（EP）穩定有重要的作用[3-5]。血管紋BLB功能障礙是自身免疫性內耳疾病、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的病理生理學研究進展。

1 耳蝸血-迷路屏障的主要成分及結構

血管紋外接螺旋韌帶位于耳蝸中階外側壁，主要包括基底細胞（basal cell,BC）、中間細胞（inter?mediate cell,IC）和邊緣細胞（marginal cell,MC）[11]。BLB是一個特殊分化的毛細血管網，位于血管紋中間層。其結構包括內皮細胞（endothelial cells, ECs）、基膜（basementmembrane,BM）、周細胞（peri?cytes,PCs）[12]及血管周圍巨噬細胞樣黑色素細胞（perivascular residentmacrophage-like melanocytes, PVM/Ms）[13]。BLB通過緊密連接、膜屏障和化學作用控制離子、液體和營養物從血液循環進入血管紋[7、14]。

正常成年C57/6J小鼠耳蝸血-迷路屏障內存在約1220-1300個周細胞（PCs），形態上有很多足突，緊貼在血管紋毛細血管壁，嵌入到基膜內[6]。血管紋PCs表達血小板源內皮生長因子受體β（plate?let-derived growth factor receptor-β,PDGFR-β）、結蛋白（desmin）、神經/膠質抗原2（neural/glial anti?gen2,NG2）和CD90（胸腺抗原-1，Thy-1）[12]。血管紋PCs含有豐富的結蛋白，屬于一種中間纖維蛋白質，可增強細胞構架機械強度且提高血管網物理彈性[12]。螺旋韌帶PCs則更多表達收縮蛋白，如平滑肌肌動蛋白（α-SMA）和原肌球蛋白[12、15]。目前研究發現，PCs對血管生成、血流調節、血管完整性和組織纖維增生有重要作用[16]。PCs通過調節ECs間緊密連接蛋白的表達調控BLB的完整性[17]。體外細胞系3D共同培養實驗研究發現PCs具有明顯促進血管新生的作用[6]。非耳蝸組織中，PCs通過直接合成膠原蛋白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）和層連粘蛋白促進基膜的形成[18]；抑制不穩定基質金屬蛋白酶(MMP)的活性，如MMP-2和MMP-9[19-20]。正常成年C57/6J小鼠耳蝸的血-迷路屏障內存在一定數量的血管周圍常駐巨噬樣色素細胞(PVM/ Ms)[21]。多數觀點認為PVM/Ms起源于耳蝸神經嵴黑色素細胞，隨著發育遷移至耳蝸血管紋[22]。PVM/ Ms的位置極為貼近邊緣細胞層下方，且多個足突與毛細血管管腔表面緊密接觸。PVM/Ms是一種混合型細胞，具有巨噬細胞和黑色素細胞的特性[4]。早期研究發現，血管紋PVM/Ms表達一系列巨噬細胞表面抗原，包括F4/80、CD68和CD11b[13]。近期研究發現，PVM/Ms還具有黑素細胞的特性，包括含有大量的黑色素和表達黑素細胞標記蛋白，例如谷胱甘肽S-轉移酶α4（Gatα4）和Kir4.1，后者為中間細胞的標記蛋白[4]。

ECs和PVM/Ms間的物理連接和信號傳導調控BLB的完整性及穩定性[4]。PVM/Ms具有黑色素細胞的特性，為抵抗有害因素在局部組織生成黑色素[23]。黑色素通過緩沖鈣，清除重金屬、外源蛋白質及脂質，促進抗氧化活性而維持組織穩態[24]。血管紋PVM/Ms具有免疫防御及修復功能，例如：清除入侵的微生物及壞死細胞；PVM/Ms可作為免疫、炎性效應細胞產生超氧化物陰離子、一氧化氮和炎性因子[25-27]。一些研究認為，其他器官組織的固有巨噬細胞在組織受損修復時能夠分化為成纖維細胞/成肌纖維細胞[28]。

BLB內基膜（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，還發現有β1和α1整合蛋白亞基[29-30]。BM中不同蛋白質相互作用形成均勻的致密板[31]。超微結構顯示基膜蛋白聚糖呈多樣化及模式化分布，且血管紋基膜帶負電荷[32]。

2 血-迷路屏障的滲透性

動物實驗發現幼年動物較成年動物的血管紋BLB滲透性更強。例如，Suzuki曾報道大鼠14日齡前其血管紋BLB未完全形成[33]。

主要通過細胞外和跨細胞兩種途徑控制血管紋BLB通透性。細胞外途徑與內皮細胞間緊密連接蛋白瞬時狀態相關?？缂毎緩桨田嫼涂鐑绕で?。BLB主要連接蛋白包括緊密連接蛋白occludin、claudins、zona occludens和黏合連接蛋白如鈣粘素（VE-cadherin）[9、34]。近期實驗表明緊密連接蛋白和黏合連接蛋白表達上調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下調可增加屏障的滲透性[4、34]。另外，跨細胞途徑滲透率依賴于轉運蛋白及轉運通道。BLB中富含轉運蛋白。例如，離體血管紋微血管質譜分析提示BLB中40%蛋白與轉運蛋白相關[9]。

3 血-迷路屏障與聽力障礙

BLB功能紊亂可導致聽力出現障礙，如噪聲性耳聾[35]、老年性耳聾[6]、自身免疫性疾病[36]、遺傳性聽力障礙[37]和炎性水腫[38]。此外，耳毒性藥物也可通過BLB進入內耳，破壞聽力功能。如順鉑類和氨基糖苷類藥物[39]。盡管這些病理條件使BLB通透性和選擇性發生改變，但是他們仍各自具有獨特的特性。

3.1噪聲性聽力損傷（NIHL）

聲損傷不但破壞感覺毛細胞、神經細胞和支持細胞，而且影響耳蝸微循環[40-43]。動物噪聲暴露后血管通透性增加、血流量減少（局部缺血）、白細胞聚集及內皮細胞受損[44]。近期研究顯示，首先聲損傷后BLB結構和分子可發生改變，包括緊密連接蛋白和黏合連接蛋白表達量減少、內皮細胞間緊密連接缺失以及血管通透性增加[45-46]。其次，接觸高強度聲音后PCs易受到損傷。PCs呈不規則發育，可從ECs正常附著位置發生遷移，從而導致BLB失去穩定性[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），導致緊密連接相關蛋白表達減少及血管滲透性增加[47]。由于PEDF控制緊密連接相關蛋白（如ZO-1和VE-cadherin）的表達，所以PVM/Ms分泌的PEDF對維持BLB的穩定性是必不可少的[4]。

3.2老年性聾

人顳骨研究中發現，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]中均發現血管紋毛細血管有一定程度的缺失。33月齡及以上的長爪沙鼠中65%-85%的血管紋毛細血管基膜增厚[50]。除此之外，還發現老年動物PCs和PVM/Ms分布密度明顯降低，伴隨血管紋明顯的形態學改變[6]。例如，年輕C57/6BJ小鼠（<3個月）含有大量扁平、細長的PCs，且與ECs緊密相連。老年C57/6BJ小鼠（>6個月）PCs較少，胞體顯著變圓，與ECs接觸減少。有研究認為此形態學改變是PCs遷移征象[51]。超微結構顯示，老年動物PCs細胞器減少，外觀成液泡狀，與ECs分離[6]。此外，老年動物中PVM/Ms也發生了變化。在年輕C57小鼠中PVM/Ms具有明顯長足突，且與血管紋毛細血管緊密連接；然而在6、9和12個月齡的小鼠中，PVM/Ms足突變短；在21月齡小鼠中PVM/Ms為扁平狀且似變形蟲狀，與毛細血管接觸減少[6]。

3.3自身免疫性聽力障礙

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

3.4遺傳性耳聾

在一些遺傳性耳聾的病理學研究中發現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，以及與耳聾相關的連接蛋白30缺失[37、55]。Nor?rie Disease主要因Ndp基因缺失導致血管紋中血管缺失引起重度感音神經性耳聾[56]。顯性白斑小鼠有重度感音神經性耳聾突變體，使血管紋中間細胞缺失[57]。顯性白斑病小鼠與老年性動物及自身免疫感音神經性聾動物的相同點是血管紋毛細血管BM增厚和IgG沉積。Light（Blt）突變體小鼠缺乏黑素細胞，導致血管紋萎縮、內淋巴電位缺失[58]。Al?port綜合征由膠原蛋白α3、α4或α5基因突變導致血管紋毛細血管BM增厚引發高頻感音神經性耳聾[55]。Nr3b2突變小鼠聽力下降與血管紋毛細血管密度下降及連接蛋白30缺失破環BLB相關[37、59]。近期研究顯示Spinster homolog2（Spns2）基因缺陷小鼠在2-3周齡時聽力敏感性和內淋巴電位迅速下降。病理學提示血管紋毛細血管及邊緣細胞邊界結構發生明顯改變[60]。

3.5炎癥反應

有假設認為炎癥因子誘導聽力障礙與血管紋毛細血管完整性及內淋巴離子平衡紊亂相關[61]。近期研究表明脂多糖誘導的中耳炎因下調緊密連接蛋白表達而破壞耳蝸BLB[10]。且有實驗驗證脂多糖促進血清熒光素通過BLB進入外淋巴[38]。Quintanilla-Dieck2013年研究鼠類發現脂多糖引發的炎癥可導致耳蝸細胞因子水平上調[62]。細胞因子水平的上調可能是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，病毒或細菌感染引起抗內皮（抗磷脂）抗體攻擊屏障上的多糖-蛋白質復合物[63]。綜合這些研究表明全身或局部炎癥可引起BLB功能紊亂，導致內穩態失衡及聽力下降。

3.6血-迷路屏障為耳毒性藥物的攻擊靶點

耳毒性藥物氨基糖苷類抗生素（如慶大霉素和阿米卡星），抗癌藥（如順鉑、卡鉑、奈達鉑和奧沙利鉑）以及循環利尿劑（如呋喃苯胺酸）具有損害人類和動物聽覺和平衡感覺的副作用[40、64-66]。耳毒性藥物可能通過BLB從血液進入內耳液體循環[67]。利尿劑或噪聲暴露破壞BLB后可增加藥物吸收率并且聽力受損明顯[68]。血管活性肽也可增加耳蝸對耳毒性藥物的吸收，如慶大霉素[69]。血管紋藥物吸收途徑涉及轉運系統及通路，包括血管紋毛細血管瞬時感受電位陽離子V 4通道（TRPV4）[70]。耳毒性藥物可引起血管紋結構損傷，引發聽力及平衡障礙。

4 總結

BLB包括ECs與大量緊密聯系的輔助細胞（PPCs和PVM/Ms）和細胞外基膜蛋白，共同組成“耳蝸血管單位（cochlearvascular unit.）”。BLB對維持內耳電解質離子平衡以及防止有毒物質大量流入血管紋具有至關重要的作用。有觀點認為，BLB的破壞與各種各樣的臨床聽力障礙相關，包括自身免疫性內耳疾病、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，但是對其在聽力和疾病中生理機能仍然知之甚少。目前相關知識的缺乏限制了BLB功能障礙相關性耳聾治療的發展。對BLB的病理生理學更好的了解是研發新型醫療干預治療BLB相關性耳聾和平衡失調所需要的基礎。

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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審核人：翟所強）

10.3969/j.issn.1672-2922.2017.02.022

國家自然科學基金面上項目（No：81170908；81470683）

張桐，碩士研究生，研究方向:耳科學

韓維舉，Email:hanweiju@aliyun.com