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原发性获得性鼻泪管阻塞发病机制的研究进展

Research progress on the pathogenesis of primary acquired nasolacrimal duct obstruction

来源期刊: 眼科学报 | 2021年11月 第36卷 第11期 921-927 发布时间: 收稿时间:2023/8/17 16:36:12 阅读量:4297
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关键词:
原发性获得性鼻泪管阻塞泪囊炎发病机制
primary acquired nasolacrimal duct obstruction dacryocystitis pathogenesis
DOI:
10.3978/j.issn.1000-4432.2020.12.05
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原发性获得性鼻泪管阻塞(primary acquired nasolacrimal duct obstruction,PANDO)是泪道阻塞性疾病中最常见的一类,好发于中老年女性,是眼科临床上的常见病、多发病,常继发急性或慢性泪囊炎的症状和体征,严重影响患者的日常工作和生活。本文对近年来PANDO可能的发病机制相关的研究进展、亟待解决的问题及未来研究的热点方向作一综述,旨在进一步加深对泪道阻塞性疾病发生发展的认识。
Primary acquired nasolacrimal duct obstruction (PANDO), which mainly occurs in the middle-aged and elderly women, is the most common type of obstructive diseases of the lacrimal duct, and it is also a common and frequently-occurring disease in ophthalmology. It constantly occurs secondary to various symptoms and signs of acute or chronic dacryocystitis, which seriously affects the daily work and life of patients. This article summarizes the research progress on the possible pathogenesis of PANDO in recent years, the urgent problems to be solved
and the hot research directions in the future, aiming to further deepen the understanding of the occurrence and development of lacrimal obstructive diseases.
眼科门诊约3 %的患者有泪道阻塞性疾病[1],阻塞可以发生在泪道的任何部位,常见于泪小点、泪小管、泪囊-鼻泪管交界处及鼻泪管下部[2],其中泪小管以下部位阻塞的病例占87%[3],常出现典型的溢泪症状。有研究[4]表明原发性获得性鼻泪管阻塞(primary acquired nasolacrimal duct obstruction,PANDO)平均年发病率为30.47/10万,其诊断标准为溢泪症状,泪道冲洗提示泪道完全阻塞,冲洗液全部从上/下泪小点返流,阻塞部位位于鼻泪管,伴有或不伴有黏性或脓性分泌物,排除其他继发因素[2]。PANDO是一种不明原因的临床综合征,该病的特征是4 0岁以上患者的溢泪症状、女性多见及容易继发急性或慢性泪囊炎的症状和体征,有可能合并或继发结膜角膜炎症或其他眼周组织感染。该病最常见的溢泪、溢脓等症状给患者的日常生活和工作带来极大影响,常伴发的急性或慢性泪囊炎作为一种感染性疾病也可向眼球及眶内蔓延,由于可能引起眼内炎等严重并发症而常被认为是内眼手术的禁忌证。
近年来,随着人民经济生活水平的提高,用眼卫生逐渐被大家重视,PANDO的诊治也得到更多研究者的关注。国内外学者在其流行病学特征和发病机制方面的探究业已取得一些进展。本文将通过文献综述的方式加深对PANDO发病机制的认识,希望为未来进一步的研究提供一些指引,并更好地指导临床上对PANDO患者的诊疗。

1 PANDO 患者的临床特征

Henr y Traquair在1941年首先描述了一种“原发”类型的慢性泪囊炎,该病具有明显的女性发病偏好并且病因未明。Linberg和McCormick于1986年首次提出“原发性鼻泪管阻塞”一词或 “ PANDO ”,他们将其描述为一种原因不明的临床综合征,其特征是好发于4 0岁以上的人群,且女性占优势[5]。既往的组织病理学研究[6-7]表明该病的特点是鼻泪管的进行性炎症反应,在此基础上进一步发生组织纤维化最终导致阻塞,由此引起的临床症状主要为不同程度的溢泪、溢脓,或可继发泪囊囊肿、急性及慢性泪囊炎等。

2 PANDO 的病理学改变

普遍认为PANDO的病理学改变主要为鼻泪管阻塞部位的慢性炎症及局部组织纤维化。Lee-Wing等[8]对166例因患PANDO而接受泪囊鼻腔吻合术(dacryocystorhinostomy,DCR)的患者进行了202次泪囊活检,结果发现65%的标本显示为慢性炎症,202例均未发现肿瘤。另一篇1986年发表的文献[9]显示PANDO早期病例表现为沿狭窄的鼻泪管全长的慢性活动性炎症,可见周围组织水肿,上皮下有致密的淋巴浆细胞浸润且压迫管腔,灶性上皮增生伴杯状细胞耗竭,偶见鳞状化生,而上皮细胞完好无损。中期病例表现为炎症过程局部消退,慢性炎症区不连续,淋巴细胞浸润明显减少,纤维组织节段性替代导管管腔,随后局灶性闭塞,上皮呈现散在的细胞巢。晚期病例表现为鼻泪管整个管腔被成熟的纤维组织所覆盖,未见上皮和腺体包涵体,慢性炎症细胞散在分布于纤维组织内。结合临床与病理结果的分析表明,炎症浸润和组织水肿导致的鼻泪管肿胀压迫先于临床慢性泪囊炎的发生。
Paulsen等[10]则研究了PANDO鼻泪管在电子显微镜下的特征,并与6个尸体对照样品进行了比较。他们将其病理改变分为轻度(炎症或纤维化仅限于上皮下黏膜的上三分之一),中度(炎症或纤维化仅限于黏膜的上半部分)及重度(炎症或纤维化涉及黏膜的全部厚度)。轻度组主要病理表现为杯状细胞和浆液腺的高分泌。中度组除炎性浸润外还表现为不同程度的分化上皮细胞丢失、上皮下成纤维细胞增多、裸露上皮局灶区和基底膜增生,泪道周围海绵体表现为管壁增厚、内膜增生、管腔狭窄甚至闭塞。重度组表现为基底膜增厚,上皮细胞鳞状化生,海绵体血管丢失,黏膜纤维化,鼻泪管管腔完全闭塞。疾病早期透射电镜可见上皮细胞基本完好,而在慢性期上皮细胞发生改变,包括形状不规则、突起长、核不规则致密、细胞质浓缩、线粒体稀疏、内质网和高尔基体的丢失,周围淋巴细胞呈退行性改变。由于泪道与鼻腔密切的毗邻关系,Mauriello等[11]对37例PANDO患者的研究中有90%的病例表现为泪道慢性炎症和纤维化改变,40%的病例表现为局灶性上皮溃疡。而他们在邻近的鼻黏膜中也发现了类似的变化,因此可以假设鼻部炎症要么继发于泪囊炎,要么泪道阻塞可能是导致鼻炎的原因。

3 PANDO 可能的发病机制

3.1 解剖参数差异

鼻泪管相关的解剖学参数差异可能与PANDO的发病有一定相关性,这种猜想的基础是流行病学依据[12],研究表明PANDO发病具有明显的女性偏向性(68%~73%)。由于鼻泪管的长度、管腔面积、位置等和种族及性别有关,Ramey等[13]回顾性分析了72例患者的计算机断层扫描(computed tomography,CT)影像学数据,结论是男性鼻泪管长度和体积明显大于女性,与年轻患者相比,5 0岁以上患者的管腔面积明显增大,且鼻泪管底部与起始段的面积之差具有统计学意义,黑人患者管腔面积明显大于白人。倪长宝等[14]对中国成年人4 0具(80侧)尸头鼻腔进行测量发现鼻泪管平均长度14.14 mm;前鼻孔内下缘交点至同侧鼻泪管开口前缘平均距离为29.00 mm,下鼻甲附着缘前端至鼻泪管开口前缘平均距离为11.07 mm。另一项纳入37例患者的研究[15]表明,鼻中隔轴向偏离的位置和角度、骨性下鼻甲与上颌窦内侧壁夹角的宽度、下鼻道测量值和异常的中鼻甲都可能是PANDO发病的相关因素。虽然有学者观察到PANDO患者的鼻泪管更狭窄,但在尸体的数据测量中发现正常的鼻泪管也存在很大解剖学变异[16],所以并没有足够的证据证明该观点。一项病例对照研究[17]发现患者和正常对照组的骨性鼻泪管体积没有显著差异,并且两组之间的范围有重叠,这意味着该因素可能与阻塞是否发生没有明显关系,而泪道阻塞的女性出现的骨性鼻泪管体积增加很可能是由于绝经后骨质管扩张导致。总的来说,骨性鼻泪管的长度、横截面积及鼻腔参数的差异对PANDO发病的影响还存在很多争议,未来需要更多影像学、尸体及活体测量的数据提供更多证据。

3.2 鼻咽部损伤

由于泪道与鼻咽部密切的毗邻关系,有研究者猜想胃食管反流病(gastroesophageal reflux disease,GERD)可能与PANDO的发生有关。在一项纳入了180例PANDO患者的研究中[18],经胃食管反流病问卷评估(reflux diagnostic questionnaire,RDQ)后发现GERD的患病率为20%(180例患者中有3 6例),而正常对照组中GERD的患病比例为10.6%(180例患者中有19例),且这种相关性在女性和6 0岁以上的患者中更高。关于二者之间发病相关性可能的机制,他们提出四种可能:1 )与慢性鼻窦炎一样,胃酸反流可能会引起直接的损伤,导致鼻泪管(nasolacrimal duct,NLD)黏膜水肿、炎症和随后的阻塞。2 )反流引起的自主神经高敏过度刺激可能导致NLD黏膜水肿,至少是暂时性的NLD闭塞。3 )幽门螺杆菌对鼻泪管组织的危害作用。4)酸反流的直接破坏作用。2018年Mehta等[19]的研究也表明与一般人群相比,GERD在PANDO患者中的患病率有所增加。不过目前已知的证据只表明二者的发病有一定相关性,但对其具体的机制还没有研究进行证明。另有文献[20]表明临床发现频繁使用游泳池也可能与PANDO的发病相关,他们认为水中的氯可能对NLD存在潜在的损伤,该观点有待进一步验证。

3.3 抗青光眼药物

一项纳入 384 例 (627 眼 )PANDO 患者的前瞻性研究中[21]发现使用抗青光眼药物组的患者(26/130,20%)中发生泪道阻塞的人明显多于对照组(24/280,8.57%;P=0.002),联合使用局部抗青光眼药物的患者出现泪道阻塞的风险显著增加,且在局部抗青光眼药物治疗的患者中,鼻泪管全长阻塞和上段阻塞更为常见。另一项关于原发性开角型青光眼(primary open-angle glaucoma,POAG)和PANDO之间相关性的研究也发现青光眼患者长期使用含噻吗洛尔的局部药物会导致患鼻泪管阻塞的风险增加,但仍需要大规模前瞻性研究来确定这种联系[22],局部药物的使用尤其是抗青光眼药物与PANDO发病之间可能的联系也是未来研究中需要继续关注的重要方面。

3.4 女性特征与激素

由于PANDO在女性中发病居多,尤其常见于围绝经期女性,所以与激素相关的因素尤为重要。Zolli和Shannon[23]对119例行DCR手术的PANDO患者进行研究,发现43%的患者过去有子宫切除或妇科病理发现的病史。因此研究者假设低水平的雌孕激素可能导致鼻泪管黏膜的干燥,致使上皮功能丧失并发生粘连,PANDO的发病类似于萎缩性阴道炎的发生过程。另一些研究则更加直接,Kashkouli等[24]的研究中均未发现52例PANDO患者与正常对照组在眼部化妆的频率、血卵泡刺激素、黄体激素、雌二醇、孕酮和睾酮组成的性激素水平(标准实验室水平)等因素存在统计学意义上的差异。
Gupta等[25]对人泪囊上皮进行免疫组织化学染色,发现雌激素和孕酮的受体为阴性,但该研究并未考虑纳入患者的血激素水平。Ali等[26]对6具尸体和5个临床泪道标本进行研究,用免疫组织化学法标记评估雌激素α、雌激素β、芳香酶、睾酮、孕酮、催产素、催乳素和生长抑素(somatostatins,SSTR)1~5受体在泪道的存在和分布情况,结果表明局部雌激素α、雌激素β和催产素表达强烈,但分布模式不同。睾酮和孕酮的表达更局限于绝经后女性泪道上皮的基底膜,而SSTR2和SSTR4仅在浅表上皮细胞的绒毛表面表达;催产素、芳香酶和催乳素在上皮下固有层和黏膜下腺体中额外表达。PANDO患者的样本显示:除催乳素的上皮免疫反应阳性外,所有激素的受体表达模式显著减少或缺失。研究者基于这些激素在细胞和分子水平对免疫调节和炎症的影响,提出了3个假说。第一,与正常男性相比,正常女性的表达水平较低,可能使局部微环境失去了这些激素的保护和抗炎作用。第二,泪道血管壁催产素表达减少可能易导致海绵体功能障碍、血管淤滞和黏膜水肿。第三,催乳素的表达定位于泪囊及鼻泪管的黏膜下腺,绝经后催乳素的减少或丢失可能导致腺体功能障碍和免疫调节功能的丧失,使相对狭窄的鼻泪管容易发生炎症和阻塞。该团队对手术获得的健康泪囊的另一篇研究[27]发现催乳素诱导蛋白(prolactin-inducible protein,PIP)的高表达,提示其在泪道免疫防御功能中可能起重要作用。PIP是一条单链多肽链,能被催乳素和雄激素上调表达。它能与多种细菌结合,抑制细菌的增殖,它还能与CD4细胞、免疫球蛋白G和锌α- 2糖蛋白的可结晶片段(fragment crystallizable,FC)部分结合,其在黏膜组织中的丰富程度提示其在黏膜免疫中的作用。泪道引流系统有很大的黏膜表面,PIP可能在一定程度上保护泪道不受眼球表面细菌的持续攻击,也介导局部免疫反应。PIP合成和调节中的紊乱可能与催乳素有关,并可能使泪道易受感染和炎症。这些可能反过来使狭窄和易受伤害的鼻泪管组织反复遭到攻击、纤维化、随后阻塞,最后出现PANDO的临床表现。
以上证据均提示全身或局部激素水平的变化及其对下游产物的影响可能与PANDO的发病有非常密切的关系,但是泪道不同部位的激素受体分布是否存在差异,为什么获得性的泪道阻塞常常发生于鼻泪管而非泪小管,不同激素及其受体在局部细胞中具体参与作用的通路等问题都需要进行更加深入的探索。

3.5 病原体与感染

PANDO总会继发急性或慢性泪囊炎,而泪道又与眼表和鼻腔相通,其中有大量潜在的致病微生物定植,那么感染性因素在PANDO的发生过程中扮演了什么角色呢?眼表感染或结膜炎的病史在鼻泪管阻塞发病之前并不少见,据报道[28],过敏性结膜炎和过敏性鼻炎与鼻泪管阻塞的发病有显著相关性(分别为OR=3.59,95%CI:3.28~3.94;OR=1.51,95%CI:1.33~1.71)。
Kashkouli等[24]对泪道1型和2型单纯疱疹病毒和人乳头瘤病毒进行免疫组织化学研究,未发现任何证据支持其与PANDO发病有关。另一项研究[7]对接受了泪囊鼻腔造口术的PANDO患者下鼻道样本和泪道活检标本中进行核酸提取,其中1 0例(20.8%)患者鼻拭子中发现冠状病毒229E(3例)、冠状病毒HKU1(2例)、呼吸道合胞病毒(2例)、冠状病毒OC43(1例)、冠状病毒NL63(1例)和腺病毒(1例)。在泪囊鼻腔造口术标本中检测到4例(8.3%)病毒基因组,包括呼吸道合胞病毒(2例)、冠状病毒HKU1(1例)和腺病毒(1例)。在呼吸道合胞病毒阳性方面,鼻黏膜拭子和泪囊活检样本之间有统计学上显著的一致,笔者认为,考虑特定病毒如呼吸道合胞病毒和腺病毒引起组织纤维化特征,病毒感染可能是病因之一。
一项包含 156 份慢性泪囊炎患者样本的研究[29]发现金黄色葡萄球菌最为常见,其次是假单胞菌属和痤疮丙酸杆菌。另外,Mitra等[30]研究单侧慢性泪囊炎患者发现需氧革兰氏阳性分离株多于革兰氏阴性分离株或厌氧分离株,其中金黄色葡萄球菌最常见,其次是铜绿假单胞菌,耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus,MRSA)在这些分离株中高度流行,可以同时形成生物膜。Eshraghi等[31]对60例急性泪囊炎和4 0例慢性泪囊炎的患者样本进行细菌培养发现52%的样本中存在革兰氏阴性菌,但只有18%的慢性泪囊炎中发现了革兰氏阴性菌。
无论是细菌还是病毒,目前并没有明确证据表明微生物感染与PANDO之间具有直接的因果关系,未来需要应用微生物组学等新技术来明确正常泪道系统中的微生物种类和数量的分布情况,并进一步阐明PANDO患者与正常人之间微生物谱系的差异。

3.6 局部细胞因子的变化

另一个值得关注的因素是泪液和泪道局部细胞因子的变化,持续存在的慢性炎症反应一定伴随着某些促炎和抗炎因子的种类和量的改变。Lee等[32]发现鼻泪管阻塞的患者术前白细胞介素(interleukin)-2、IL-6,IL-10、血管内皮生长因子(vascular endothelial growth factor,VEGF)和成纤维细胞生长因子(fibroblast growth factor,FGF)-2浓度明显高于对照组。术后随访期间,行DCR组泪液中大多数炎性细胞因子(IL-1β,IL-2,IL-6,VEGF和FGF-2)高于对照组,但在取出泪道支架后迅速降至对照组水平。与手术结果良好的眼相比,复发患者泪液中转化生长因子(transforming growth factor,TGF)-β2和FGF-2水平较高。在Ali等[33]的研究中,收集泪液进行多重酶联免疫吸附试验,评估了总共3 5种与炎症、血管生成和伤口愈合有关的因子,结果提示与非患病对照相比,PANDO患者患病眼眼泪中10种促炎细胞因子显著上调,包括基质金属蛋白酶9(metalloproteinase, MMP-9)、血清蛋白E 1、IL-6、肝细胞生长因子(hepatocyte growth factor,HGF)、VEGF-A和VEGF-R2、血小板内皮细胞黏附分子(platelet-endothelial cell adhesion molecule,PECAM-1)、C反应蛋白(c-reactive protein,CRP)、趋化因子配体2 (chemokine ligand,CCL2)和血小板衍生生长因子-AA(platelet-derived growth factor,PDGF-AA)。与非患病对照相比,3种抗炎细胞因子在PANDO患者患病眼中显著上调,包括粒细胞集落刺激因子(granulocyte-colony stimulating factor,G-CSF)、视黄醇结合蛋白4 (retinol binding protein,RBP4)和金属蛋白酶组织抑制剂-1 (tissue inhibitor of metalloproteinases,TIMP-1)。患病患者的对侧眼和健康受试者的对照眼之间没有显著差异。基于细胞因子的显著改变,分析显示PANDO发病机制中涉及的生物学途径包括了炎症、血管生成、凋亡负调节、细胞增殖和激素调节等途径。
亦有研究表明泪液中炎症因子的改变与其他眼表疾病和眼部异常相关,例如干眼及睑板腺功能障碍[34-36],而不同的受试者和采样方法检测出的细胞因子的种类与数量也不尽相同[37-38]。即便如此,细胞因子的改变仍是需要关注的重要因素之一,期待未来有更精确的方法明确正常人与PANDO患者细胞因子谱的差异,并寻找关键的信号通路来明确该病发生发展中核心的分子生物学机制。

4 结语

PANDO是一种病因不明的泪道阻塞性疾病,尽管泪道的再通或改道手术可解决大部分患者的溢泪、溢脓问题,但从解剖学及分子生物学等不同层面探索发病机制,寻找致病的关键性通路对于PANDO的早期防控具有十分重要的意义。期待在未来的临床及基础研究中能更加科学深入地探究鼻泪管阻塞的始动因素,为治疗PANDO提供新的思路和干预靶点。

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1、国家自然科学基金 (81800866);中山大学中山眼科中心五个五临床专科建设项目 (3030901010071);中山大学 中山眼科中心教学改革项目 ( JX3030604014)。
This work was supported by the National Natural Science Foundation (81800866), Five and Five Clinical Specialty Construction Projects of Zhongshan Ophthalmic Center, Sun Yat-sen University (3030901010071), and Teaching Reform Project of Zhongshan Ophthalmic Center, Sun Yat-sen University ( JX3030604014), China.()
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