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MMP-2在单纯疱疹病毒性角膜炎中的研究进展

Research progress of MMP-2 in herpes simplex keratitis

来源期刊： 眼科学报 | 2025年9月 第40卷 第9期： 763-767 发布时间：2025-09-28 收稿时间：2025/9/25 14:35:45 阅读量：97
作者：
於莹,
杜海涛,
关键词：
角膜明胶酶A金属蛋白酶组织抑制剂2单纯疱疹病毒性角膜炎
cornea MMP-2 TIMP-2 HSK
DOI：
10.12419/24102904
收稿时间：
2024-10-29 
修订日期：
2024-12-28 
接收日期：
2025-02-27 
角膜因其特有的内部有序排列结构具有高度透明性，是眼前部重要的屈光间质，又因其缺乏血液供应，角膜疾病恢复周期较长、病情易反复出现，严重影响患者的视力和日常生活。基质金属蛋白酶(matrix metalloproteinase, MMP)通过参与组织蛋白降解重塑、血管生成、炎症免疫反应等，在肺纤维化、动脉粥样硬化等众多疾病中具有重要作用，其中MMP-2(明胶酶A)在眼部相关疾病中的作用也逐渐受到关注。单纯疱疹病毒性角膜炎具有高度致盲性，反复发作会导致角膜失去透明性，角膜混浊逐渐加重，最终导致失明。研究者通过对MMP-2在HSK、角膜溃疡中的病理作用机制进行分析研究，发现MMP-2的特异性抑制药物在角膜炎中具有一定的临床应用前景，未来或可从本文的研究角度出发，适当增加相关的药物治疗研发，解决目前治疗的局限性，以期为角膜疾病患者带来新的有效治疗方案。
The cornea has a high degree of transparency due to its unique internal orderly arrangement structure, and as a major refractive media in the anterior eye. However, due to its lack of blood supply, the recovery period of corneal diseases is long and the condition is prone to recurrence, corneal diseases seriously affecting the patient's vision and daily life. Matrix Metalloproteinases play an important role in many diseases, such as pulmonary fibrosis and atherosclerosis, by participating in tissue protein degradation and remodelling, angiogenesis, inflammatory immune response, etc. Among them, the role of MMP-2 in ocular diseases has also been gradually explored and studied. Herpes simplex virus keratitis is highly blinding, and repeated attacks can cause the cornea to lose transparency, gradually worsen corneal opacity, ultimately resulting in blindness. By analysing the mechanism of MMP-2 in herpesvirus keratitis and corneal ulcers, researchers were found that specific inhibitions of MMP-2 have certain clinical application prospects in keratitis. In the future, from the perspective of this study, it may be appropriate to increase the research and development of related drug treatments, solve the limitations of current treatments, and bring new effective treatment options for corneal disease patients.

文章亮点

1. 关键发现

 • MMP-2 在单纯疱疹病毒性角膜炎和溃疡角膜中的表达分布反映了炎症反应的变化程度，应用 MMP-2 抑制药物可减轻局部角膜炎症程度并减低其并发症发生率。

2. 已知与发现

 • 单纯疱疹病毒性角膜炎因其高复发率和致盲性，严重危害全球患者的生活质量，传统治疗方式具有较多局限性。MMP-2 相关抑制药物在单纯疱疹病毒性角膜炎中的实验研究，开拓了临床药物研发的新思路。

3. 意义与改变

 • 深入了解 MMP-2 在单纯疱疹病毒性角膜炎中的作用机制，有助于研制 MMP-2 特异性抑制剂，为角膜疾病的优化诊疗找到新的突破口。

       角膜是眼部重要的屈光间质，其内胶原纤维的有序排列、角膜内皮细胞的正常运作及无血管结构共同维持了角膜的透明性，营养供给来自房水和角膜缘血管网，同时角膜富含丰富的神经，眼表的异常刺激会导致反射性的闭眼和泪液分泌，从而保护眼表结构不受损伤。鉴于其特殊结构，角膜疾病病程周期长且极易反复，长期迁延不愈会导致角膜透明性状发生改变，同时，病程中伴随强烈的眼部刺激症状，严重影响患者的视力及生活质量。单纯疱疹病毒性角膜炎（herpes simplex keratitis, HSK）是全世界致盲率最高的感染性角膜疾病，且复发率极高，患者饱受其困扰，是亟待重视的疾病。本文详细阐述了HSK的临床表现、发病机制，并分析总结了相关特异性抑制药物的研究进展，为临床诊治与新药物的研发提供理论支持。

1 概述

       MMPs是一类锌依赖性蛋白水解酶家族，迄今为止，已经发现了2 8种蛋白酶，根据结构和功能不同，将其分为6类：明胶酶、胶原酶、基质分解素、基质溶解素、金属弹性蛋白酶和膜型基质金属蛋白酶(membrane-type matrix metalloproteinases, MTMMPs)[1]。MMPs广泛存在于人体的各种组织内，参与调节组织蛋白降解及重塑、血管生成、细胞迁移、炎症免疫反应等，与肺纤维化[2]、心肌梗死[3]、动脉粥样硬化[4]等多种疾病密切相关。明胶酶又称Ⅳ型胶原酶，包括MMP-2(明胶酶A)和MMP-9(明胶酶B)，存在于细胞外基质(extracellular matrix, ECM)中，能够降解Ⅳ、Ⅴ、Ⅶ和Ⅹ型胶原、弹性蛋白、层粘连蛋白、纤连蛋白和蛋白聚糖等[5]众多ECM成分，介导组织的生理及病理过程。关于MMP-2在神经系统、心血管系统、呼吸系统等常见疾病中的作用被广泛研究，在干眼症[6]、圆锥角膜[7]等眼部疾病中也逐渐发现MMP-2的身影。

2 病理机制

       MMP-2由前肽、催化结构域、铰链区和血红素结合蛋白结构域组成，生理条件下，前肽通过半胱氨酸巯基与催化中心的Zn2+特异性结合，使MMP-2保持无活性的酶原状态，催化结构域中含有3个纤连蛋白重复序列，能够识别变性胶原，增强MMP-2与明胶及明胶类似物的结合能力，MMP-2的生物学特性与催化中心的特殊结构密不可分[1, 5]。金属蛋白酶组织抑制剂-2(tissue inhibitor of matrix metalloproteinase 2, TIMP-2)- 膜型基质金属蛋白酶-1(MT1-MMP)复合物作为受体通过TIMP-2 C末端与proMMP-2血红素结合蛋白结构域结合，形成三级蛋白质复合体，附近的MT1-MMP裂解proMMP-2，从而激活分子量62kDa、具有催化活性的MMP-2 [8]，见图1。研究证实，MMP-2与TIMP-2的比例失衡，是引起许多疾病的关键因素[9]；亦有实验证明，TIMP-2对MMP-2的调控具有双重性，低浓度时TIMP-2形成的蛋白质复合体对MMP-2具有激活作用；当浓度过高时，TIMP-2与MMP-2直接结合产生抑制作用[10-11]。

图1 MMP-2的激活过程
Figure 1 activation process of MMP-2

20251011160616_8139.png

3 单纯疱疹病毒性角膜炎

3.1 介绍

       单纯疱疹病毒性角膜炎(HSK)是由疱疹病毒I型HSV-1导致的免疫相关性角膜疾病，具有较高的致盲率和复发率，在一些发展中国家，HSV-1的患病率高达90%[12]。HSV-1是嗜神经性的双链DNA病毒，初次感染人体后，病毒潜伏在三叉神经节内[13]，在机体免疫力降低或发生应激条件下，潜伏的病毒再次激活，导致病毒性角膜炎复发，基质型角膜炎反复发作会导致角膜神经损伤及感觉受损，造成角膜溃疡、新生血管、瘢痕形成等，破坏稳态平衡、角膜透明性改变，HSK的全球发病例数约为每年180万[14]，其中约4万人会出现视力障碍或失明[15-16]。因此，了解HSK的发生、发展过程，从疾病机制角度进行针对性的治疗，是HSK防治的新思路。

3.2 临床表现

       原发性HSK常见于幼儿，主要表现为全身感染症状，眼部受累时仅出现角膜上皮病变且症状不典型。复发性HSK以上皮型为主，早期出现疼痛、摩擦感、流泪等眼部刺激症状并伴随角膜知觉减退，及时有效地治疗上述症状会缓解，部分未经控制的患者可逐渐出现深层角膜溃疡。出现基质型HSK时，角膜呈水肿状态，可见上皮大范围缺损和局部炎性浸润灶，反复发作可导致角膜变薄、新生血管化及瘢痕形成，少数病情迅速进展也可导致角膜穿孔[17]。

3.3 发病机制

       在HSK病情进展中，MMP-2具有重要作用。炎症环境刺激静息的角膜基质细胞分化为成纤维细胞[18]，角膜上皮细胞和基质成纤维细胞产生proMMP-2并分泌到ECM中，炎症相关因子，如白介素-1（Interleukin-1，IL-1），肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）等的激活介导MMP-2表达上调和TIMP-2的下调[19]，活性氧(reactive oxygen species, ROS)被认为是MMP-2的激活剂，从而启动ECM的胶原降解与重塑过程，见图2。Yang等[20]通过HSK小鼠模型证明TNF-α与MMP-2的表达呈正相关，且在人角膜上皮细胞培养物中证实TNF-α对MMP-2的调控通过FAK/ERK途径实现，MMP-2的表达在病程中呈波动状态，感染早期MMP-2表达轻度升高，角膜上皮愈合后表达减低，发展至角膜溃疡后表达量再次明显升高。Ke等[21]的实验发现HSV-1感染小鼠角膜早期，MMP-2的表达和激活对角膜炎症具有积极作用。另一实验中[22]，HSK小鼠角膜组织中，角膜上皮、基质和炎性细胞中MMP-2和TIMP-2呈强染色，且靠近溃疡区和坏死处染色更显著，说明MMP-2与TIMP-2在HSK的病情进展过程中具有关键作用。角膜新生血管也与HSK明显相关，早期抑制新生血管可以减轻HSK的严重程度。研究发现[23]，MMP-2和TIMP-2与血管生成的调控有关，上调的MMP-2诱导血管内皮生长因子(vascular endothelial growth factor,VEGF)生成增多，基质降解产生的游离血管内皮细胞向VEGF富集处迁移形成新生血管[24]，MMP-2主要分布在新生血管细胞浸润区，且VEGF与MMP-2的分布相近[25]。

图2 HSV-1对角膜的侵袭
Figure 2 HSV-1 invasion of cornea

20251011160702_5548.png

4 治疗

       HSK的治疗原则为抑制病毒复制、减少复发、减轻瘢痕。目前，常规治疗HSK的方法包括抗病毒药物(阿昔洛韦、更昔洛韦滴眼液或眼膏)，与免疫相关的复发性HSK联合使用糖皮质激素(激素)类药物，应用抗生素滴眼液预防细菌感染，角膜穿孔或瘢痕修复影响视力时进行角膜移植手术，同时提倡预防性口服阿昔洛韦减少HSK的复发，积极控制诱发因素也是必要措施。
      然而，长期高剂量使用抗病毒滴眼液存在对角膜上皮的损伤，造成视物模糊、异物感等表现[26]，且口服抗病毒药物具有肾毒性损害，不建议长期应用。激素类滴眼液长期使用会引起眼压升高、并发性白内障、继发性青光眼等并发症，因此眼部激素类药物需谨慎使用。而角膜移植因其费用高、供体少等特点并不能适用于所有患者。因此，从HSK的病理机制角度出发，研制特异性抑制药物，具有临床应用前景。

4.1 多西环素

       多西环素为半合成四环素类抗生素，FDA已批准其作为系统性MMPs抑制剂用于治疗牙周炎和酒糟鼻[27]。冠状动脉支架患者术后使用多西环素可降低血清中MMPs浓度并减轻炎症反应[28]，在糖尿病小鼠模型中应用低剂量多西环素可逆转高糖诱导的氧化应激并抑制MMP-2活性[29]。在He等[30]的实验中发现，多西环素可能通过下调MMP-2、VEGF的表达，抑制翼状胬肉成纤维细胞血管生成，从而延缓人翼状胬肉的病情进展。同样，硫芥诱导的兔眼损伤模型中，在急性损伤期和新生血管阶段均可在兔角膜组织中检测到显著升高的MMP-2，使用多西环素干预的实验组MMP-2含量降低明显，且角膜损伤的严重程度和新生血管的增生程度明显减轻，然而多西环素在出现新生血管的病损角膜无明显治疗效果[31]，说明多西环素可用于角膜炎的前期预防性治疗。以上相关研究结果提示，多西环素是强效的MMP抑制剂和ROS清除剂，其对病灶局部炎症反应程度的降低及新生血管的抑制作用，或可成为早期HSK的有效治疗药物。

4.2 脂氧素A4

       脂氧素A4属于内源性花生四烯酸代谢物，通过调节机体免疫细胞，降低组织过度损伤并控制慢性炎症反应，发挥抗炎作用[32]，其可能通过抑制细胞内ROS积累和ROS/ERK途径，下调MMP-2转录的表达[33]。用脂氧素A4处理碱烧伤大鼠角膜2周后，角膜组织中浸润的炎症细胞数量减少、炎症相关因子IL-1β、IL-6及VEGF、MMP-9的表达明显降低，与载体治疗组相比角膜混浊、新生血管的程度显著降低[34]，脂氧素A4除直接抑制VEGF、明胶酶活性外，还可拮抗血管生成。Zhou等[35]的研究也提出脂氧素A4通过抑制兔角膜成纤维细胞对IL-1β的应答，从而降低MMP-2的表达，抑制角膜基质胶原降解。此外前期的研究发现，在角膜创伤愈合过程中，脂氧素作为生长因子的中间代谢产物，通过刺激角膜上皮细胞增殖，促进创伤修复[34]。脂氧素不仅可以降低炎症因子的表达、抑制胶原降解，在创伤修复过程中也起到重要作用，其多重治疗作用或可减少眼部用药的种类，从而减少多种药物的使用对角膜的毒性作用。

4.3 TIMP衍生物 

       肽是调节各种生物反应和生理过程的重要生物学成分，环状TIMP肽模拟物(ZHAWOC7726)因其低毒性和膜渗透性被研究并筛选出来[36]，ZHAWOC7726在相对低浓度下呈现高活性状态，对MMP-2、9、13具有高特异性抑制活性作用。ZHAWOC7726能够下调铜绿假单胞菌感染的猪角膜MMP-9表达并抑制其活性，减少角膜成纤维细胞的异常生成，而未经治疗的对照组角膜厚度显著减少、角膜混浊及瘢痕增生更明显[19, 37]，说明环状TIMP肽模拟物可用于预防感染性角膜炎角膜溃疡穿孔及瘢痕的形成。然而，目前尚未有TIMP2衍生物特异性抑制MMP-2的相关报道，鉴于MMP-2在角膜炎疾病进展中的作用，研制TIMP2衍生物具有可观的临床应用前景。

4.4 羊膜移植

       羊膜是胎盘膜的最内层无血管、半透明的薄膜组织，也是人体最厚的基底膜。羊膜可能通过下调转化生长因子-β（transforming growth factor-β，TGF-β)的表达和活性，抑制角膜细胞向角膜成纤维细胞转化，进一步干扰MMPs的生成，发挥其抗炎、抗血管生成及抗纤维化作用[38]，羊膜亦可通过对MT1-MMP的抑制进而参与MMP-2的调控[39]。人羊膜移植的HSK小鼠实验发现，羊膜具有促进角膜上皮愈合作用，羊膜移植后感染的角膜基质水肿减轻，角膜血管化症状逐渐改善，角膜穿孔发病率较对照组明显降低[40]。与角膜移植不同，羊膜取材量大、较易保存且费用相对较低，能够更好地降低角膜溃疡和穿孔风险，提高角膜炎患者的预后。

5 总结

       HSK是全球发达和发展中国家感染性失明的首要疾病，其新发率和复发率极高，病情反复发作导致剧烈的眼部刺激症状和角膜透明度下降，进而严重影响患者的视力和生活，而传统治疗方式往往预后不良。大量研究发现MMP-2在炎症反应过程中具有重要作用，本文研究探讨了MMP-2的激活方式及其可能在HSK病程中的作用机制，从病理机制的角度出发，分析、归纳并总结了MMP-2的相关抑制药物在角膜炎病程中的不同作用途径，以期为HSK提供有效治疗的新思路，从而制定出更加优化的诊疗策略，为饱受HSK疾病困扰的患者带来光明的希望。

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1、黑龙江省博士后科研启动金(LBH-Q21031)。
This work was supported byHeilongjiang Postdoctoral Scientific Research Developmental Fund (LBH-Q21031).This work was supported byHeilongjiang Postdoctoral Scientific Research Developmental Fund (LBH-Q21031). ( )
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