上皮細(xì)胞在氣道變態(tài)反應(yīng)性疾病中的作用

Role of airway epithelial cells in the pathogenesis on respiratory allergic diseases

王勇聰，彭華，汪建(廣州軍區(qū)廣州總醫(yī)院耳鼻咽喉科，廣東 廣州 510010)

[關(guān)鍵詞]氣道上皮細(xì)胞；變態(tài)反應(yīng)性疾病；發(fā)病機(jī)制

呼吸道變態(tài)反應(yīng)性疾病的發(fā)病率在臨床上呈日益增高的趨勢(shì)，嚴(yán)重影響人們的生活和工作[1]。常見的呼吸道變態(tài)反應(yīng)性疾病包括：變態(tài)反應(yīng)性鼻炎(allergic rhinitis，AR)、支氣管哮喘(bronchial asthma，BA)以及過(guò)敏性咳嗽等。上、下氣道的變態(tài)反應(yīng)性疾病既相互關(guān)聯(lián)，又有其特殊的組織特異性。近年來(lái)，氣道上皮細(xì)胞在呼吸道變態(tài)反應(yīng)性疾病發(fā)病機(jī)制中的作用越來(lái)越受到人們的關(guān)注和重視。呼吸道上皮細(xì)胞分布于整個(gè)上下氣道，是阻擋吸入性過(guò)敏原入侵機(jī)體的第一道防線，同時(shí)也具有一定的免疫調(diào)節(jié)功能。氣道上皮細(xì)胞的研究為呼吸道變態(tài)反應(yīng)的治療提供新思路，本文綜述如下。

1氣道上皮細(xì)胞的黏液纖毛清除功能

呼吸道上皮中的杯狀細(xì)胞可分泌黏液，黏膜下層中的黏液腺可分泌黏液和漿液。呼吸道黏膜的每個(gè)上皮細(xì)胞約有200條纖毛，通過(guò)規(guī)律的擺動(dòng)將呼吸道分泌的黏液向咽部推移。吸入性變應(yīng)原通過(guò)氣道上皮進(jìn)入機(jī)體是氣道過(guò)敏性疾病發(fā)生的始動(dòng)因素。某些呼吸道病毒，如人類鼻病毒(human rhinovirus，HRV)、呼吸道合胞病毒(respiratory syneytial virus，RSV)等可誘導(dǎo)Th2型細(xì)胞因子分泌，這是引起呼吸道變態(tài)反應(yīng)性疾病發(fā)生或加重的重要因素[2]。柴油顆粒、粉塵等空氣中污染物則是誘發(fā)AR或BA的重要佐劑[3]。而呼吸道上皮細(xì)胞的黏液纖毛清除功能可直接將大部分吸入性變應(yīng)原、呼吸道的病原體、粉塵等清除體外，極大地減少了呼吸道變態(tài)反應(yīng)性疾病的發(fā)生概率。

另一方面，呼吸道黏膜變態(tài)反應(yīng)性炎癥可使氣道上皮細(xì)胞

的黏液纖毛清除功能減退。劉建國(guó)等[4]研究發(fā)現(xiàn)變應(yīng)原暴露會(huì)引起大鼠鼻黏膜細(xì)胞纖毛面積減少、排列紊亂,有的纖毛粘集成團(tuán)、向不同方向傾倒,上皮纖毛和絨毛等多數(shù)超微結(jié)構(gòu)發(fā)生進(jìn)行性損害,隨著變應(yīng)原暴露時(shí)間的延長(zhǎng)大鼠會(huì)出現(xiàn)鼻涕排除障礙。變應(yīng)原暴露、病毒感染或基因突變皆可引起哮喘患者氣道上皮細(xì)胞的纖毛結(jié)構(gòu)異常、擺動(dòng)頻率下降，進(jìn)而降低黏液纖毛的清除功能[5]。

2氣道上皮細(xì)胞的物理屏障功能

氣道表面由連續(xù)的上皮細(xì)胞覆蓋，通過(guò)緊密連接、半橋粒和粘著連接而形成一個(gè)完整的氣道黏膜屏障，將空氣中的有害物質(zhì)和黏膜下層的免疫細(xì)胞分離開來(lái)。病毒感染、煙霧等可直接損傷氣道上皮細(xì)胞，誘發(fā)或加重AR或BA的癥狀[6]。而變應(yīng)原則通過(guò)其蛋白水解酶活性破壞氣道上皮細(xì)胞間的連接，以及釋放炎癥因子、下調(diào)粘連蛋白的表達(dá)、直接損傷細(xì)胞等多種途徑造成氣道上皮細(xì)胞物理屏障功能破壞。塵螨等帶有蛋白水解活性酶的變應(yīng)原可直接水解氣道上皮細(xì)胞之間的連接，也可通過(guò)蛋白酶活化受體-2(protease activated receptor-2，PAR-2)的激活間接破壞氣道上皮細(xì)胞之間的連接[7-8]。細(xì)胞連接的粘附分子 (cell adhesion molecule,CAM)依賴于Ca2+才能發(fā)揮作用，而帶有酶活性變應(yīng)原可競(jìng)爭(zhēng)性結(jié)合Ca2+，導(dǎo)致氣道上皮細(xì)胞間的連接分離[9]。跨膜鈣粘附蛋白是緊密連接和粘著連接的重要組成成分，在連接復(fù)合體中起著支架作用。而體內(nèi)、外研究實(shí)驗(yàn)發(fā)現(xiàn)呼吸道變應(yīng)性疾病患者氣道上皮細(xì)胞之間的跨膜鈣粘附蛋白等多種連接蛋白表達(dá)減少[10-11]。氣道上皮細(xì)胞間連接的完整性遭到破壞導(dǎo)致變應(yīng)原輕易地穿過(guò)氣道上皮黏膜層，并與黏膜下層的免疫細(xì)胞相接觸，隨后啟動(dòng)免疫應(yīng)答反應(yīng)[12]。

氣道上皮細(xì)胞的物理屏障功能障礙還促進(jìn)了呼吸道重塑。在正常呼吸道上皮細(xì)胞中，表皮生長(zhǎng)因子(epithelial growth factors，EGF)從細(xì)胞的基底側(cè)分泌，而表皮生長(zhǎng)因子受體(epithelial growth factors receptors，EGFR)位于細(xì)胞的頂面，兩者被氣道上皮細(xì)胞形成的物理屏障分隔開來(lái)[13]。變應(yīng)原刺激可導(dǎo)致氣道上皮細(xì)胞表達(dá)的EGF、EGFR增加[14-15]。當(dāng)氣道上皮細(xì)胞的物理屏障功能出現(xiàn)障礙后，細(xì)胞基底側(cè)分泌的EGF能與位于氣道上皮細(xì)胞頂面的EGFR相結(jié)合，進(jìn)而促進(jìn)氣道上皮組織增厚、重構(gòu)[13]。呼吸道變態(tài)反應(yīng)性疾病患者的上皮細(xì)胞高表達(dá)的骨膜素可促進(jìn)嗜酸性粒細(xì)胞、肌纖維細(xì)胞釋放轉(zhuǎn)化生長(zhǎng)因子-β(transforming growth factor-β,TGF-β)，后者可促使纖維母細(xì)胞分化為成熟的纖維細(xì)胞并合成大量的膠原蛋白和細(xì)胞外基質(zhì)，導(dǎo)致氣道上皮細(xì)胞向間充質(zhì)轉(zhuǎn)化，引起呼吸道增厚、組織重構(gòu)[13,16]。而氣道上皮細(xì)胞向間充質(zhì)轉(zhuǎn)化后又可導(dǎo)致跨膜鈣粘附蛋白生成減少，進(jìn)一步破壞氣道上皮細(xì)胞的物理屏障功能[12]。

變應(yīng)原引起呼吸道上皮細(xì)胞黏膜屏障功能障礙在機(jī)體對(duì)變應(yīng)原易感性中起到重要作用[12]。變應(yīng)原導(dǎo)致的氣道上皮細(xì)胞間連接破壞、呼吸道重構(gòu)、氧自由基生成增多、氣道高反應(yīng)等均可引起機(jī)體對(duì)變應(yīng)原的易感性增加。研究還發(fā)現(xiàn)變應(yīng)原可通過(guò)激活核因子κB(nuclear factor kappa B，NF-κB)途徑導(dǎo)致氣道上皮細(xì)胞表達(dá)大量的易感基因,如：PCDH1[17]，CDHR3[18]，SMAD3，HLA-DR，IL1RL1[19]。反復(fù)變應(yīng)原暴露可促進(jìn)小鼠氣道上皮細(xì)胞的蛋白酪氨酸磷酸酶SHP2基因表達(dá)增加，而SHP2能夠調(diào)控小鼠氣道上皮細(xì)胞TGF-β1的產(chǎn)生[20]。氣道上皮細(xì)胞表達(dá)大量易感基因增加了機(jī)體對(duì)吸入性變應(yīng)原、空氣中粉塵等有害物質(zhì)的易損傷性，同時(shí)也導(dǎo)致氣道上皮細(xì)胞的自我修復(fù)和分化形成完整的氣道上皮細(xì)胞屏障的功能下降，進(jìn)一步促進(jìn)呼吸道變態(tài)反應(yīng)性疾病的發(fā)生[12]。

3氣道上皮細(xì)胞的免疫功能

近年來(lái)研究發(fā)現(xiàn)人類呼吸道上皮細(xì)胞具有活躍的免疫功能。氣道上皮細(xì)胞表面表達(dá)多種模式識(shí)別受體(pattern recognition receptors，PRRs)，包括：Toll樣受體(Toll-like receptors,TLRs)、PARs-2、NOD樣受體(NOD-like receptors,NLRs)、C型凝集素受體(C-type lectins receptors，CTLRs)、EGFR等。吸入性變應(yīng)原激活氣道上皮細(xì)胞表面的PRPs后，通過(guò)激活NF-κB途徑促進(jìn)多種炎癥相關(guān)的細(xì)胞因子基因表達(dá)以及多種細(xì)胞因子、趨化因子的釋放，如：胸腺基質(zhì)淋巴細(xì)胞生成素(thymic stromal lymphopoietin，TSLP)、白細(xì)胞介素-33(interleukin-33，IL-33)、白細(xì)胞介素25(interleukin-25，IL-25)、血管內(nèi)皮生長(zhǎng)因子-A(vascular endothelial growth factor-A,VEGF-A)、血管內(nèi)皮生長(zhǎng)因子-C(vascular endothelial growth factor-C,VEGF-C)、粒細(xì)胞集落刺激因子(granulocyte，monocyte colony stimulating factor，GM-CSF)、CC趨化因子2(CC chemokine ligand 2，CCL2)、CC趨化因子20(CC chemokine ligand 20，CCL20)、嗜酸性粒細(xì)胞活化趨化因子、干細(xì)胞因子(stem cell factor, SCF)、細(xì)胞間粘附分子1(intracellular adhesion molecule-1，ICAM-1)、白細(xì)胞介素6(interleukin-6，IL-6)、白細(xì)胞介素8(interleukin-8，IL-8)等的釋放，隨后觸發(fā)呼吸道變態(tài)反應(yīng)性炎癥的發(fā)生或加重[13，21]。

樹突狀細(xì)胞作為抗原遞呈細(xì)胞，在變應(yīng)原誘導(dǎo)的呼吸道變態(tài)反應(yīng)性疾病的發(fā)病機(jī)制中起著重要的橋梁作用。氣道上皮細(xì)胞可通過(guò)釋放細(xì)胞因子控制樹突狀細(xì)胞的抗原遞呈功能[22]。變應(yīng)原刺激氣道上皮細(xì)胞后分泌的CCL2、CCL20等能促使血液中的單核細(xì)胞游出至黏膜下層，分泌的VEGF-A和VEGF-C能促進(jìn)黏膜基底層血管和淋巴管的生成[23]。而新生的血管和淋巴管對(duì)單核細(xì)胞的游出以及攜帶變應(yīng)原的樹突狀細(xì)胞向淋巴結(jié)轉(zhuǎn)移提供了便利[13]。氣道上皮細(xì)胞分泌的IL-33、IL-25、TSLP、GM-CSF等細(xì)胞因子可抑制樹突狀細(xì)胞表達(dá)Th1型免疫反應(yīng)相關(guān)的細(xì)胞因子IL-12，同時(shí)促進(jìn)Th2型免疫反應(yīng)相關(guān)的多種細(xì)胞因子，如：IL-4、IL-6、白三烯C4(leukotriene C4，LTC4)等的釋放[13]。游出的單核細(xì)胞在氣道上皮細(xì)胞分泌的趨化因子、細(xì)胞因子、氧自由基等的共同作用下分化成為成熟的樹突狀細(xì)胞并攜帶變應(yīng)原進(jìn)入淋巴結(jié)，隨后刺激淋巴結(jié)內(nèi)的原始Th0細(xì)胞向Th2細(xì)胞分化，抑制其向Th1細(xì)胞方向分化，導(dǎo)致Th1/Th2失衡[13]。氣道上皮細(xì)胞間充質(zhì)轉(zhuǎn)化后也可持續(xù)激活樹突狀細(xì)胞并促進(jìn)成熟樹突狀細(xì)胞向淋巴結(jié)轉(zhuǎn)移[24]。

氣道上皮細(xì)胞分泌的TSLP、IL-25、IL-33、ICAM-1、SCF等細(xì)胞因子除了招募、激活樹突狀細(xì)胞外，同時(shí)也能直接激活其他的免疫相關(guān)細(xì)胞，包括嗜酸性粒細(xì)胞、嗜堿性粒細(xì)胞、肥大細(xì)胞、T淋巴細(xì)胞等。TSLP能激活樹突狀細(xì)胞產(chǎn)生IL-8和嗜酸性粒細(xì)胞活化趨化因子，進(jìn)而刺激CD4+T細(xì)胞產(chǎn)生Th2型細(xì)胞因子[25]。IL-25通過(guò)激活樹突狀細(xì)胞促進(jìn)Th2型細(xì)胞因子的產(chǎn)生[26]。氣道上皮細(xì)胞分泌的IL-33能與巨噬細(xì)胞、肥大細(xì)胞、嗜堿性粒細(xì)胞、CD4+T細(xì)胞等免疫相關(guān)細(xì)胞表面的相應(yīng)受體ST2受體相結(jié)合，促進(jìn)這些細(xì)胞釋放大量的Th2型細(xì)胞因子和趨化因子，在過(guò)敏性炎癥的免疫調(diào)節(jié)中起重要作用[27-28]。IL-33與嗜堿性粒細(xì)胞表面ST2受體結(jié)合后還能促進(jìn)IgE受體介導(dǎo)的組胺釋放[28]。研究發(fā)現(xiàn)激活I(lǐng)L-33/ST2軸不僅調(diào)節(jié)多種細(xì)胞產(chǎn)生Th2型細(xì)胞因子，還導(dǎo)致氣道的高反應(yīng)[29]。呼吸道黏膜上皮細(xì)胞產(chǎn)生的IL-33在缺乏T細(xì)胞和B細(xì)胞的情況下也能誘導(dǎo)過(guò)敏反應(yīng)[30]。氣道上皮細(xì)胞來(lái)源的SCF可促進(jìn)肥大細(xì)胞的成熟并向呼吸道黏膜浸潤(rùn)[31]。嗜酸性粒細(xì)胞活化趨化因子有促進(jìn)嗜酸性粒細(xì)胞在呼吸道黏膜浸潤(rùn)的作用[32]。AR或BA臨床癥狀消失后仍有少量ICAM-1、嗜酸性粒細(xì)胞存在于氣道黏膜內(nèi)，導(dǎo)致呼吸道黏膜仍然處于高敏狀態(tài)[33]。

氣道上皮細(xì)胞除了通過(guò)分泌的細(xì)胞因子產(chǎn)生免疫反應(yīng)，也可通過(guò)產(chǎn)生的多種損傷相關(guān)分子模式(damage-associated molecular patterns，DAMP)誘導(dǎo)免疫應(yīng)答。變應(yīng)原刺激呼吸道黏膜引起黏膜血漿外滲，隨后導(dǎo)致氣道上皮細(xì)胞缺氧、水腫，并釋放大量的DAMP，包括自由基、三磷酸腺苷、尿酸、溶血磷脂酸等，這些DAMP可通過(guò)激活TLRs、NLRs等模式識(shí)別受體，誘導(dǎo)免疫應(yīng)答[34]。氧自由基(reactive oxygen species，ROS)可通過(guò)損傷氣道上皮細(xì)胞的生物膜、核酸、蛋白或者減少抗氧化劑的表達(dá)而導(dǎo)致機(jī)體對(duì)過(guò)敏原易感性增加[35]，也可通過(guò)誘導(dǎo)氣道上皮細(xì)胞表達(dá)細(xì)胞因子和EGFR而觸發(fā)變態(tài)反應(yīng)性疾病的發(fā)生或加重[36]。三磷酸腺苷、尿酸、溶血磷脂酸等DAMP分子通過(guò)NF-κB途徑激活樹突狀細(xì)胞以及其他相關(guān)免疫細(xì)胞，同時(shí)通過(guò)促進(jìn)氣道上皮細(xì)胞進(jìn)一步釋放TSLP、GM-CSF、IL-33、IL-25等細(xì)胞因子，進(jìn)一步導(dǎo)致Th1/Th2失衡[13，37-38]。呼吸道變應(yīng)性疾病患者的氣道上皮細(xì)胞大量表達(dá)誘生型一氧化氮合成酶，進(jìn)一步加重呼吸道黏膜炎癥[39]。

4總結(jié)與展望

呼吸道黏膜上皮細(xì)胞具有黏液纖毛清除功能、物理屏障功能以及多種免疫功能，氣道上皮細(xì)胞結(jié)構(gòu)及功能的異?？善茐臍獾赖墓逃忻庖?，導(dǎo)致免疫系統(tǒng)的異常信號(hào)傳導(dǎo)、氣道重塑以及氣道高反應(yīng)性，在呼吸道變應(yīng)性疾病的發(fā)生和發(fā)展中起著重要作用。雖然近年來(lái)人們對(duì)氣道上皮細(xì)胞在呼吸道變應(yīng)性疾病發(fā)病機(jī)制中的作用日益重視，但還有很多未明之處有待進(jìn)一步研究。以氣道上皮細(xì)胞為靶點(diǎn)的研究在呼吸道變應(yīng)性疾病的機(jī)制及治療中具有重要的意義[1]。

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(編輯：周小林)

[收稿日期]2014-11-18[修回日期] 2014-11-29

[通訊作者]汪建,E-mail:13889909318@139.com

[基金項(xiàng)目]國(guó)家自然科學(xué)基金項(xiàng)目資助(2013046)

doi:10.11659/jjssx.11E014025

[中圖分類號(hào)]R562.25；R765.21

[文獻(xiàn)標(biāo)識(shí)碼]B

[文章編號(hào)]1672-5042(2015)03-0333-04