神經(jīng)生長(zhǎng)因子對(duì)單純皰疹病毒性角膜炎的治療作用與機(jī)制

黎玥 徐建江

·綜述·

神經(jīng)生長(zhǎng)因子對(duì)單純皰疹病毒性角膜炎的治療作用與機(jī)制

黎玥 徐建江

單純皰疹病毒性角膜炎(HSK)是由單純皰疹病毒所致的角膜炎，是世界范圍內(nèi)致盲的一個(gè)重要原因，而其復(fù)發(fā)性及對(duì)阿昔洛韋日漸增加的耐藥性讓醫(yī)師在治療過(guò)程中感到棘手，尋求可替代的藥物成為未來(lái)的趨勢(shì)。神經(jīng)生長(zhǎng)因子(NGF)現(xiàn)認(rèn)為不僅存在于神經(jīng)系統(tǒng)中，也存在于多種組織中，并且作為一種免疫調(diào)節(jié)因子發(fā)揮作用。NGF及其受體也存在于角膜上。近年有學(xué)者在動(dòng)物模型以及臨床上將其用于HSK的治療，取得了很好的效果。本文將NGF對(duì)HSK的作用，以及其影響角膜損傷修復(fù)、角膜神經(jīng)再生、Toll樣受體通路及維持病毒潛伏狀態(tài)等相關(guān)機(jī)制進(jìn)行綜述，為后續(xù)研究方向提供參考。(中國(guó)眼耳鼻喉科雜志，2017，17：436-440)

神經(jīng)生長(zhǎng)因子；單純皰疹病毒性角膜炎；角膜損傷修復(fù)；角膜神經(jīng)再生；Toll樣受體；病毒潛伏

單純皰疹病毒(herpes simplex virus，HSV)是一種高度流行的病原體，特別是HSV-1，據(jù)估計(jì)全世界60%～80%的人群都感染了該病毒[1]，而單純皰疹病毒性角膜炎(herpes simplex virus keratitis，HSK)是由HSV所引起的角膜感染，絕大多數(shù)為HSV-1。因HSV的潛伏后再活化所致慢性病程而導(dǎo)致永久性角膜瘢痕、視力損傷甚至致盲，被認(rèn)為是世界范圍內(nèi)致盲的一個(gè)主要原因[2]。據(jù)保守估計(jì)，全球HSK的發(fā)病數(shù)粗算可達(dá)每年150萬(wàn)，其中包括4萬(wàn)可致嚴(yán)重的單眼視力損害或盲[3]。據(jù)2014年在我國(guó)的多中心研究[4]顯示，患有HSK的比例達(dá)0.11%。HSK無(wú)論何種類型，幾乎都會(huì)用抗病毒藥物，其中阿昔洛韋的應(yīng)用最為廣泛，引發(fā)了人們對(duì)其病毒耐藥性的關(guān)注。近年已有人從皰疹性角膜炎的免疫正?；颊咧蟹蛛x到高達(dá)6.4%的對(duì)阿昔洛韋耐藥的HSV-1[5]。還有值得注意的是，現(xiàn)今的治療方法并不能完全治愈該病，而只是減輕癥狀并且?guī)椭S持病毒的潛伏狀態(tài)。即使使用抗病毒藥物，HSK也可復(fù)發(fā)[6]。因此，無(wú)論是HSV再激活所致HSK的易復(fù)發(fā)性還是HSV可能對(duì)抗病毒藥產(chǎn)生的耐藥性，都提示需要去探索HSK的發(fā)病機(jī)制并且尋求可替代的治療藥物或方法。

神經(jīng)營(yíng)養(yǎng)因子(neurotrophic factors，NT)是一類具有促進(jìn)神經(jīng)元存活、生長(zhǎng)和抗凋亡作用的蛋白質(zhì)，其中神經(jīng)生長(zhǎng)因子(nerve growth factor，NGF)作為最早且研究最為廣泛的神經(jīng)營(yíng)養(yǎng)因子，有兩大受體：一是與其他NT成員共享的低親和力受體p75NTR；二是特異性的高親和力酪氨酸受體trkA[7]。NGF現(xiàn)認(rèn)為不僅存在于神經(jīng)系統(tǒng)中，也廣泛存在于其他組織中，如血管、膀胱、平滑肌、視網(wǎng)膜及角膜等；還作為一種免疫調(diào)節(jié)因子發(fā)揮作用，如肥大細(xì)胞、巨噬細(xì)胞、T細(xì)胞及B細(xì)胞在免疫過(guò)程中都可產(chǎn)生NGF[8]。NGF及其受體也存在于角膜上，關(guān)于NGF與角膜疾病的研究也層出不窮。基于HSV的嗜神經(jīng)性及NGF應(yīng)用于HSK治療的有效性，本綜述將聚焦于NGF應(yīng)用于HSK的作用，以及其作用的機(jī)制。

1 NGF對(duì)HSK的作用

HSK現(xiàn)分為4種主要類型：感染性上皮型角膜炎、神經(jīng)營(yíng)養(yǎng)性角膜病變、基質(zhì)型角膜炎、內(nèi)皮型角膜炎[9]。絕大多數(shù)HSK都是上皮型，以樹枝狀或地圖樣潰瘍?yōu)樘攸c(diǎn)；基質(zhì)型可由上皮型發(fā)展而來(lái)，發(fā)病率隨著復(fù)發(fā)而提高，而長(zhǎng)期復(fù)發(fā)的角膜炎往往會(huì)有神經(jīng)營(yíng)養(yǎng)性的因素參與其中；內(nèi)皮型則少見，且動(dòng)物模型基本不會(huì)涉及內(nèi)皮型的造模，故本文中提及的HSK是除內(nèi)皮型外的HSK。

有研究[10]發(fā)現(xiàn)，若在HSV感染的兔子模型中系統(tǒng)性應(yīng)用抗NGF抗體，會(huì)誘導(dǎo)HSK的再?gòu)?fù)發(fā)。另有研究證實(shí)在兔子中局部應(yīng)用NGF相較對(duì)照組，HSK的程度在臨床上及實(shí)驗(yàn)室參數(shù)上(包括裂隙燈下評(píng)分、用免疫學(xué)和分子學(xué)方法評(píng)估病毒復(fù)制情況等)都有明顯的減輕，其效果與阿昔洛韋組差異沒(méi)有統(tǒng)計(jì)學(xué)意義；反之，局部使用抗NGF抗體則會(huì)誘導(dǎo)更嚴(yán)重的角膜炎，并且10例中有2例發(fā)生了致死的HSV腦炎[11]。甚至有學(xué)者在臨床上對(duì)阿昔洛韋局部和系統(tǒng)應(yīng)用抵抗的HSK所致角膜潰瘍某患者，連續(xù)使用23 d NGF滴眼液治療可致完全的角膜愈合[12]。更有許多研究[13-15]證實(shí)了NGF有幫助神經(jīng)營(yíng)養(yǎng)性潰瘍愈合的作用。從上述研究看，即可發(fā)現(xiàn)NGF在病毒性潰瘍和神經(jīng)營(yíng)養(yǎng)性潰瘍的修復(fù)、減少病毒復(fù)制和擴(kuò)散以及防止HSK再?gòu)?fù)發(fā)等方面都有有益的作用，雖說(shuō)在人身上的證據(jù)還遠(yuǎn)遠(yuǎn)不足，但這些結(jié)果都預(yù)示著NGF有著很大潛力成為治療HSK的新選擇。

2 NGF與其受體在角膜上的表達(dá)

前面已介紹NGF有2種受體，總的來(lái)說(shuō)，大多數(shù)NGF介導(dǎo)的生物學(xué)活性(從分化/激活到增生/存活)都是依賴于trkA受體通路介導(dǎo)的，后續(xù)激活MAPK-Ras-Erk通路、磷脂酶Cy1、P3I激酶和短核轉(zhuǎn)導(dǎo)蛋白等[16]。p75NTR獨(dú)立誘導(dǎo)特殊的轉(zhuǎn)導(dǎo)途徑，該途徑包括NF-κB和c-Jun激酶，并產(chǎn)生更多的神經(jīng)酰胺，這些因子可介導(dǎo)基因的轉(zhuǎn)錄或程序性細(xì)胞死亡[17]。以下研究證實(shí)了NGF及其受體在角膜上的表達(dá)。

Lambiase等[18-19]發(fā)現(xiàn)在正常生理狀態(tài)下，人和大鼠的角膜產(chǎn)生并儲(chǔ)存NGF，主要由上皮、角膜細(xì)胞和內(nèi)皮產(chǎn)生；在體外培養(yǎng)的人和大鼠角膜上皮細(xì)胞也可產(chǎn)生儲(chǔ)存和分泌NGF，同樣也表達(dá)trkA。因此，作者認(rèn)為在同一細(xì)胞上NGF及其受體的同時(shí)表達(dá)，提示角膜上皮細(xì)胞很有可能是通過(guò)自分泌或旁分泌機(jī)制來(lái)維持其存活并發(fā)揮作用。Qi等[20]用免疫熒光染色的方法發(fā)現(xiàn)NGF的免疫活性僅位于人類角膜緣基底上皮細(xì)胞小部分，而在整個(gè)角膜和角膜緣高于基底細(xì)胞的上皮層都未檢測(cè)到活性；trkA受體的分布與Lambiase等的研究結(jié)果相同，即主要局限在基底上皮細(xì)胞，角膜及角膜緣的基質(zhì)層都未檢測(cè)到活性；而對(duì)于p75NTR，免疫熒光染色使得角膜和角膜緣基底層和緊鄰著的上皮層顯色，再上層的上皮層不顯色，在角膜緣區(qū)域的基質(zhì)細(xì)胞包括血管內(nèi)皮細(xì)胞、神經(jīng)纖維和成纖維細(xì)胞都為強(qiáng)顯色。由此可以看出，NGF對(duì)HSK產(chǎn)生相應(yīng)的作用并非偶然，而是有相應(yīng)的結(jié)構(gòu)及分子學(xué)基礎(chǔ)。

3 現(xiàn)有的機(jī)制進(jìn)展

現(xiàn)有如下的相關(guān)研究，可能是NGF對(duì)HSK產(chǎn)生作用的基礎(chǔ)。

3.1 NGF促進(jìn)角膜損傷的修復(fù) 在HSV感染的初始，多以點(diǎn)狀的上皮病變?yōu)楸憩F(xiàn)，故大多數(shù)的HSK都伴有上皮的損害，而較深的角膜潰瘍和基質(zhì)型角膜炎都可以累及角膜基質(zhì)。角膜損傷的修復(fù)是一系列十分復(fù)雜的連鎖反應(yīng)，涉及上皮細(xì)胞、基質(zhì)角膜細(xì)胞、角膜神經(jīng)、淚腺、淚膜和免疫細(xì)胞之間的細(xì)胞因子調(diào)節(jié)[21]。

NGF可以從多個(gè)方面參與修復(fù)過(guò)程。首先，在體外培養(yǎng)的人類角膜上皮中，NGF可以促進(jìn)角膜上皮細(xì)胞的增殖和分化，且這種作用可能是通過(guò)Art和Erk信號(hào)通路促進(jìn)細(xì)胞周期蛋白D的激活，從而影響到人類角膜上皮的細(xì)胞周期進(jìn)程(從G1期轉(zhuǎn)為S期)來(lái)實(shí)現(xiàn)的[22-23]。其次，角膜細(xì)胞可轉(zhuǎn)化為特殊的成纖維細(xì)胞樣角膜細(xì)胞及成肌纖維細(xì)胞參與愈合過(guò)程[21]。有研究在體外培養(yǎng)的成纖維細(xì)胞樣角膜細(xì)胞上發(fā)現(xiàn)了NGF，trkA-NGFR和p75NTR的表達(dá)，NGF的加入可以促進(jìn)這些細(xì)胞分化為成肌纖維細(xì)胞、促進(jìn)遷移,還可促使金屬蛋白酶-9(MMP-9)的表達(dá)和活性及3D膠原晶格結(jié)構(gòu)的收縮[24]。在成年母雞的體內(nèi)實(shí)驗(yàn)中發(fā)現(xiàn)，NGF的處理促進(jìn)了角膜上皮遷移，從而幫助了更快的愈合，且這個(gè)效應(yīng)是通過(guò)MMP-9的上調(diào)和β4整合素的裂解實(shí)現(xiàn)的[25]。最終，愈合過(guò)程的終止是需要成肌纖維細(xì)胞的缺失，在體外NGF可能作為成肌纖維細(xì)胞凋亡的誘導(dǎo)因子，且此過(guò)程是通過(guò)p75NTR介導(dǎo)的，當(dāng)trkA/p75比例中p75占主導(dǎo)時(shí)則會(huì)傾向于該過(guò)程[26]。所以，NGF可以幫助角膜上皮細(xì)胞的增殖、分化、遷移，并進(jìn)一步調(diào)節(jié)成肌纖維細(xì)胞來(lái)促使角膜損傷的修復(fù)。

3.2 角膜神經(jīng)纖維再生 正常的角膜神經(jīng)分布對(duì)維持正常的角膜結(jié)構(gòu)和功能十分重要，而皰疹性角膜炎是最為常見的致使角膜感覺(jué)損傷的原因。研究發(fā)現(xiàn)，HSK眼中角膜感覺(jué)損傷與基底膜下神經(jīng)叢的明顯減少密切相關(guān)，隨著HSK的復(fù)發(fā)，除了內(nèi)皮型角膜炎，角膜上皮下的神經(jīng)叢形態(tài)也會(huì)逐漸破壞，且這些神經(jīng)分布的變化是與角膜淺表上皮細(xì)胞密度和大小的變化密切相關(guān)的[27-29]。而神經(jīng)纖維的再生在神經(jīng)營(yíng)養(yǎng)性角膜炎中的作用更不用多說(shuō)。

NGF在神經(jīng)纖維再生方面起到了作用。早在20世紀(jì)，NGF在體外刺激軸突生長(zhǎng)的作用即被證實(shí)[30]。TrkA受體缺乏的敲除基因小鼠的角膜神經(jīng)密度和角膜感覺(jué)都是下降的，提示角膜神經(jīng)分布的形成是NGF依賴性的[31]。在實(shí)驗(yàn)性眼科手術(shù)致使角膜神經(jīng)損傷的動(dòng)物模型中，局部或系統(tǒng)性應(yīng)用NGF可幫助修復(fù)基底膜下的神經(jīng)叢，且術(shù)后早期NGF蛋白和mRNA的變化是與角膜神經(jīng)叢的密度相關(guān)[32-34]。而在辣椒素誘導(dǎo)的大鼠角膜神經(jīng)損傷模型中，NGF局部滴眼可以改善角膜神經(jīng)損傷后的一系列變化，如角膜愈合速度、神經(jīng)分布和淚液分泌等[35]。由此可以看出，NGF對(duì)角膜神經(jīng)的修復(fù)作用已在動(dòng)物模型上多次得到證實(shí)，但在人體中使用效果的證據(jù)尚不足。

3.3 NGF參與調(diào)節(jié)TLR通路 HSV在致病過(guò)程中，先激活一系列固有免疫反應(yīng)。其中，Toll樣受體(toll-like receptors，TLR)作為重要的一類模式識(shí)別受體(pattern recognition receptor, PRR)在感染過(guò)程中發(fā)揮作用。TLR2可識(shí)別HSV-1糖蛋白gB和gH/gL[36-37]，TLR3可識(shí)別HSV-1 dsRNA[38]，TLR9可識(shí)別包括HSV-1在內(nèi)的病毒基因CpG島[39]。TLR在HSK中的作用具體見表1。一方面，TLR識(shí)別HSV-1誘導(dǎo)了免疫防御意在從角膜上清除病毒；另一方面，由于激活了固有免疫，TLR也可能加重免疫反應(yīng)從而導(dǎo)致角膜破壞[40]。故TLR是HSV感染角膜中重要的一環(huán)，而NGF是否對(duì)TLR信號(hào)通路產(chǎn)生影響從而調(diào)節(jié)角膜的免疫呢？

在單核細(xì)胞中，當(dāng)炎癥刺激物活化TLR產(chǎn)生促炎癥反應(yīng)時(shí)，NGF的trkA受體上調(diào)，NGF通過(guò)激活trkA信號(hào)通路，影響TLR通路而下調(diào)炎癥因子的產(chǎn)生和誘導(dǎo)抗炎因子的生成，從而減輕炎癥反應(yīng)[41]。也有研究者[42]直接用NGF刺激單核細(xì)胞，發(fā)現(xiàn)了NGF通過(guò)trkA受體激活NF-κB進(jìn)一步調(diào)節(jié)炎癥因子。在樹密細(xì)胞(DC)中，刺激TLR4信號(hào)可以通過(guò)p38 MAPK和NF-κB通路的激活增加NGF及其受體p75NTR的表達(dá)[43]。VKC起源的結(jié)膜上皮細(xì)胞中TLR4的表達(dá)相對(duì)上升而TLR9的表達(dá)相對(duì)下降，使用NGF后可誘導(dǎo)強(qiáng)烈的TLR4和適當(dāng)?shù)腡LR9表達(dá)上調(diào)，并可以檢測(cè)到IL-10的顯著下降，不伴有IFN-γ、IL-4和IL-12 p40的明顯變化[44]。NGF可能幫助調(diào)節(jié)TLR相關(guān)的炎癥反應(yīng)，但現(xiàn)未有研究在角膜上直接證實(shí)，故此不失為未來(lái)研究的一個(gè)重要方向。

表1 HSK與TLR之間的研究

注：HCEC為人角膜上皮細(xì)胞

3.4 NGF與HSV潛伏狀態(tài) HSV的嗜神經(jīng)性使其可潛伏于周圍神經(jīng)中，當(dāng)某些條件下如紫外線照射、壓力、發(fā)熱、低溫、焦慮等[51-53]，HSV可再激活從而誘導(dǎo)HSK的復(fù)發(fā)。這也是對(duì)于HSK的治療讓人感到棘手的原因之一。

前面已提到在動(dòng)物模型中應(yīng)用抗NGF抗體可以誘導(dǎo)HSK的再?gòu)?fù)發(fā)[10]，而在體外NGF的撤退可以誘導(dǎo)感覺(jué)和交感神經(jīng)元中HSV-1的再激活也早就被證實(shí)[54]，故添加NGF常作為保持HSV潛伏狀態(tài)的方法之一，但具體的機(jī)制的確鮮有人研究。在體外不成熟的神經(jīng)元中，NGF撤退通?？烧T導(dǎo)凋亡信號(hào)通路[55]，而caspase-3作為p75NGF受體下游重要的因子，它的抑制物可減少HSV-1的再激活，直接激活caspase-3可促進(jìn)HSV-1的再激活[56]。Camarena等[57]發(fā)現(xiàn)在神經(jīng)細(xì)胞中，NGF通過(guò)激活trkA受體來(lái)持續(xù)性激活PI3-K通路對(duì)于維持HSV-1潛伏狀態(tài)十分關(guān)鍵，該通路被打斷后，即使是短暫性的，也可引起病毒的再激活。期待有更多的研究闡述其中的機(jī)制，這必將對(duì)復(fù)發(fā)性HSK的機(jī)制和相關(guān)治療有所幫助。

4 結(jié)語(yǔ)

綜上所述，NGF對(duì)HSK的愈合、減少病毒的復(fù)制和擴(kuò)散及防止其復(fù)發(fā)具有有益作用，NGF及其受體在角膜上的表達(dá)為其提供結(jié)構(gòu)基礎(chǔ)，相關(guān)的機(jī)制可能涉及促進(jìn)角膜損傷修復(fù)、幫助角膜神經(jīng)再生、影響HSV通過(guò)TLR介導(dǎo)角膜炎癥及維持病毒潛伏狀態(tài)等幾個(gè)方面，但至今為止相關(guān)的研究較少，故需要大量的研究進(jìn)一步探討NGF與HSK的聯(lián)系，有望對(duì)臨床治療給出新的提示。

[1] Roizman B. Herpes simplex viruses. Fields Virology. 5th ed[M]. Philadelphia: Lippincott, Williams and Wilkins, 2007.

[2] Kaye S, Choudhary A. Herpes simplex keratitis[J]. Prog Retin Eye Res, 2006,25(4):355-380.

[3] Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update[J]. Surv Ophthalmol, 2012,57(5):448-462.

[4] Song X, Xie L, Tan X, et al. A multi-center, cross-sectional study on the burden of infectious keratitis in China[J]. PLoS One, 2014,9(12):e113843.

[5] Duan R, de Vries RD, Osterhaus AD, et al. Acyclovir-resistant corneal HSV-1 isolates from patients with herpetic keratitis[J]. J Infect Dis, 2008,198(5):659-663.

[6] Azher TN, Yin XT, Tajfirouz D, et al. Herpes simplex keratitis: challenges in diagnosis and clinical management[J]. Clin Ophthalmol, 2017,11:185-191.

[7] Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction[J]. Annu Rev Biochem, 2003,72:609-642.

[8] Chang E, Im YS, Kay EP, et al. The role of nerve growth factor in hyperosmolar stress induced apoptosis[J]. J Cell Physiol, 2008,216(1):69-77.

[9] Holland EJ, Schwartz GS. Classification of herpes simplex virus keratitis[J]. Cornea, 1999,18(2):144-154.

[10] Hill JM, Garza HH, Helmy MF, et al. Nerve growth factor antibody stimulates reactivation of ocular herpes simplex virus type 1 in latently infected rabbits[J]. J Neurovirol, 1997,3(3):206-211.

[11] Lambiase A, Coassin M, Costa N, et al. Topical treatment with nerve growth factor in an animal model of herpetic keratitis[J]. Graefes Arch Clin Exp Ophthalmol, 2008,246(1):121-127.

[12] Mauro C, Pietro L, Emilio CC. The use of nerve growth factor in herpetic keratitis: a case report[J]. J Med Case Rep, 2007,1:124.

[13] Lambiase A, Rama P, Bonini S, et al. Topical treatment with nerve growth factor for corneal neurotrophic ulcers[J]. N Engl J Med, 1998,338(17):1174-1180.

[14] Bonini S, Lambiase A, Rama P, et al. Topical treatment with nerve growth factor for neurotrophic keratitis[J]. Ophthalmology, 2000,107(7):1347-1351, 1351-1352.

[15] Tan MH, Bryars J, Moore J. Use of nerve growth factor to treat congenital neurotrophic corneal ulceration[J]. Cornea, 2006,25(3):352-355.

[16] Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair[J]. Annu Rev Neurosci, 2001,24:1217-1281.

[17] Frade J M, Rodriguez-Tebar A, Barde Y A. Induction of cell death by endogenous nerve growth factor through its p75 receptor[J]. Nature, 1996,383(6596):166-168.

[18] Lambiase A, Manni L, Bonini S, et al. Nerve growth factor promotes corneal healing: structural, biochemical, and molecular analyses of rat and human corneas[J]. Invest Ophthalmol Vis Sci, 2000,41(5):1063-1069.

[19] Lambiase A, Bonini S, Micera A, et al. Expression of nerve growth factor receptors on the ocular surface in healthy subjects acid during manifestation of inflammatory diseases[J]. Invest Ophthalmol Vis Sci, 1998,39(7):1272-1275.

[20] Qi H, Chuang EY, Yoon K, et al. Patterned expression of neurotrophic factors and receptors in human limbal and corneal regions[J]. Mol Vis, 2007,13:1934-1941.

[21] Wilson SE, Mohan RR, Mohan RR, et al. The corneal wound healing response: cytokine-mediated interaction of the epithelium, stroma, and inflammatory cells[J]. Prog Retin Eye Res, 2001,20(5):625-637.

[22] You LT, Kruse FE, Volcker HE. Neurotrophic factors in the human cornea[J]. Invest Ophthalmol Vis Sci, 2000,41(3):692-702.

[23] Hong J, Qian T, Le Q, et al. NGF promotes cell cycle progression by regulating D-type cyclins via PI3K/Akt and MAPK/Erk activation in human corneal epithelial cells[J]. Mol Vis, 2012,18:758-764.

[24] Micera A, Lambiase A, Puxeddu I, et al. Nerve growth factor effect on human primary fibroblastic-keratocytes: possible mechanism during corneal healing[J]. Exp Eye Res, 2006,83(4):747-757.

[25] Blanco-Mezquita T, Martinez-Garcia C, Proenca R, et al. Nerve growth factor promotes corneal epithelial migration by enhancing expression of matrix metalloprotease-9[J]. Invest Ophthalmol Vis Sci, 2013,54(6):3880-3890.

[26] Micera A, Puxeddu I, Balzamino BO, et al. Chronic nerve growth factor exposure increases apoptosis in a model of in vitro induced conjunctival myofibroblasts[J]. PLoS One, 2012,7(10):e47316.

[27] Nagasato D, Araki-Sasaki K, Kojima T, et al. Morphological changes of corneal subepithelial nerve plexus in different types of herpetic keratitis[J]. Jpn J Ophthalmol, 2011,55(5):444-450.

[28] Hamrah P, Sahin A, Dastjerdi MH, et al. Cellular changes of the corneal epithelium and stroma in herpes simplex keratitis: an in vivo confocal microscopy study[J]. Ophthalmology, 2012,119(9):1791-1797.

[29] Hamrah P, Cruzat A, Dastjerdi MH, et al. Corneal sensation and subbasal nerve alterations in patients with herpes simplex keratitis: an in vivo confocal microscopy study[J]. Ophthalmology, 2010,117(10):1930-1936.

[30] Recio-Pinto E, Rechler MM, Ishii DN. Effects of insulin, insulin-like growth factor-II, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons[J]. J Neurosci, 1986,6(5):1211-1219.

[31] de Castro F, Silos-Santiago I, Lopez D AM, et al. Corneal innervation and sensitivity to noxious stimuli in trkA knockout mice[J]. Eur J Neurosci, 1998,10(1):146-152.

[32] Ma K, Yan N, Huang Y, et al. Effects of nerve growth factor on nerve regeneration after corneal nerve damage[J]. Int J Clin Exp Med, 2014,7(11):4584-4589.

[33] Joo MJ, Yuhan KR, Hyon JY, et al. The effect of nerve growth factor on corneal sensitivity after laser in situ keratomileusis[J]. Arch Ophthalmol, 2004,122(9):1338-1341.

[34] Chen L, Wei RH, Tan DT, et al. Nerve growth factor expression and nerve regeneration in monkey corneas after LASIK[J]. J Refract Surg, 2014,30(2):134-139.

[35] Lambiase A, Aloe L, Mantelli F, et al. Capsaicin-induced corneal sensory denervation and healing impairment are reversed by NGF treatment[J]. Invest Ophthalmol Vis Sci, 2012,53(13):8280-8287.

[36] Cai M, Li M, Wang K, et al. The herpes simplex virus 1-encoded envelope glycoprotein B activates NF-kappaB through the Toll-like receptor 2 and MyD88/TRAF6-dependent signaling pathway[J]. PLoS One, 2013,8(1):e54586.

[37] Leoni V, Gianni T, Salvioli S, et al. Herpes simplex virus glycoproteins gH/gL and gB bind Toll-like receptor 2, and soluble gH/gL is sufficient to activate NF-kappaB[J]. J Virol, 2012,86(12):6555-6562.

[38] Lim HK, Seppanen M, Hautala T, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk[J]. Neurology, 2014,83(21):1888-1897.

[39] Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA[J]. Nature, 2000,408(6813):740-745.

[40] Rolinski J, Hus I. Immunological aspects of acute and recurrent herpes simplex keratitis[J]. J Immunology Research, 2014,2014:1-9.

[41] Prencipe G, Minnone G, Strippoli R, et al. Nerve growth factor downregulates inflammatory response in human monocytes through TrkA[J]. J Immunol, 2014,192(7):3345-3354.

[42] Datta-Mitra A, Kundu-Raychaudhuri S, Mitra A, et al. Cross talk between neuroregulatory molecule and monocyte: nerve growth factor activates the inflammasome[J]. PLoS One, 2015,10(4):e121626.

[43] Jiang Y, Chen G, Zheng Y, et al. TLR4 signaling induces functional nerve growth factor receptor p75NTR on mouse dendritic cells via p38MAPK and NF-κB pathways[J]. Mol Immunol, 2008,45(6):1557-1566.

[44] Micera A, Stampachiacchiere B, Normando EM, et al. Nerve growth factor modulates toll-like receptor (TLR) 4 and 9 expression in cultured primary VKC conjunctival epithelial cells[J]. Mol Vis, 2009,15:2037-2044.

[45] Takeda S, Miyazaki D, Sasaki S, et al. Roles played by toll-like receptor-9 in corneal endothelial cells after herpes simplex virus type 1 infection[J]. Invest Ophthalmol Vis Sci, 2011,52(9):6729-6736.

[46] Jin X, Qin Q, Chen W, et al. Expression of toll-like receptors in the healthy and herpes simplex virus-infected cornea[J]. Cornea, 2007,26(7):847-852.

[47] Sarangi PP, Kim B, Kurt-Jones E, et al. Innate recognition network driving herpes simplex virus-induced corneal immunopathology: role of the toll pathway in early inflammatory events in stromal keratitis[J]. J Virol, 2007,81(20):11128-11138.

[48] Zheng M, Klinman DM, Gierynska M, et al. DNA containing CpG motifs induces angiogenesis[J]. Proc Natl Acad Sci U S A, 2002,99(13):8944-8949.

[49] Li H, Zhang J, Kumar A, et al. Herpes simplex virus 1 infection induces the expression of proinflammatory cytokines, interferons and TLR7 in human corneal epithelial cells[J]. Immunology, 2006,117(2):167-176.

[50] Wuest T, Austin BA, Uematsu S, et al. Intact TRL 9 and type I interferon signaling pathways are required to augment HSV-1 induced corneal CXCL9 and CXCL10[J]. J Neuroimmunol, 2006,179(1/2):46-52.

[51] Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health[J]. Nat Rev Immunol, 2005,5(3):243-251.

[52] Wheeler CJ. Pathogenesis of recurrent herpes simplex infections[J]. J Invest Dermatol, 1975,65(4):341-346.

[53] Varnell ED, Kaufman HE, Hill JM, et al. Cold stress-induced recurrences of herpetic keratitis in the squirrel monkey[J]. Invest Ophthalmol Vis Sci, 1995,36(6):1181-1183.

[54] Wilcox CL, Johnson EM. Nerve growth-factor deprivation results in the reactivation of latent herpes-simplex virus in vitro[J]. J Virol, 1987,61(7):2311-2315.

[55] Kaplan DR, Miller FD. Neurotrophin signal transduction in the nervous system[J]. Curr Opin Neurobiol, 2000,10(3):381-391.

[56] Hunsperger EA, Wilcox CL. Caspase-3-dependent reactivation of latent herpes simplex virus type 1 in sensory neuronal cultures[J]. J Neurovirol, 2003,9(3):390-398.

[57] Camarena V, Kobayashi M, Kim JY, et al. Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons[J]. Cell Host Microbe, 2010,8(6):551.

2017-01-22)

(本文編輯 諸靜英)

訃告

Therapeuticeffectsandrelatedmechanismsofnervegrowthfactoronherpessimplexviruskeratitis

LIYue,XUJian-jiang.

DepartmentofOphthalmology,EyeEarNoseandThroatHospitalofFudanUniversity,Shanghai200031,China

XU Jian-jiang, Email: jianjiangxu@126.com

Herpes simplex keratitis (HSK), an important cause of blindness world-wide, is the keratitis caused by herpes simplex viruses. What make doctors feel troublesome are its recurrences and increased resistance to acyclovir. So, looking for alternative drugs is needed. Researches showed that nerve growth factor (NGF) exists in nervous systems as well as other tissues like cornea, and also plays a role as an immunologic mediator. Recently researchers topically used NGF for the treatment of HSK on animal models and patients, getting unexpected great improvement. In this review, the effects of NGF on HSK and the potential mechanisms, including helps of corneal wound healing and corneal nerve regeneration, influence of Toll-like receptor pathways and maintenance of latency, will be discussed and concluded. (Chin J Ophthalmol and Otorhinolaryngol,2017,17:436-440)

Nerve growth factor; Herpes simplex virus keratitis; Corneal wound healing; Corneal nerve regeneration; Toll-like receptors; Virus latency

復(fù)旦大學(xué)附屬眼耳鼻喉科醫(yī)院眼科 上海 200031

通迅作者：徐建江(Email： jianjiangxu@126.com)

10.14166/j.issn.1671-2420.2017.06.016