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. 2022 Nov 29;51(5):613–625. [Article in Chinese] doi: 10.3724/zdxbyxb-2022-0603

生长因子在眼的发育及眼部疾病调控中的作用

Roles of growth factors in eye development and ophthalmic diseases

Xiaojie WANG 1, Qi HUI 1, Zi JIN 1, Fengqin RAO 1, Lei JIN 1, Bingjie YU 1, Joshua BANDA 1, Xiaokun LI 1
PMCID: PMC10264994  PMID: 36581579

Abstract

生长因子是一类由多种细胞分泌的活性物质，作为信使调控细胞的迁移、增殖和分化。多种生长因子参与眼组织的发育及眼部疾病的生理、病理过程。血管内皮生长因子、碱性成纤维细胞生长因子等介导糖尿病性视网膜病、脉络膜新生血管、白内障、糖尿病性黄斑水肿以及其他视网膜疾病的发生和发展。神经生长因子、睫状神经营养因子、胶质细胞源性神经营养因子、色素上皮衍生因子、粒细胞集落刺激因子等对视神经损伤有较好的修复作用。生长因子还与近视的发病密切相关，成纤维细胞生长因子、转化生长因子-β、胰岛素样生长因子影响巩膜厚度变化并调控近视的发生与发展。本文综述了生长因子参与眼的发育和眼部病理生理过程的研究进展，旨在揭示生长因子与眼部疾病的关联，为生长因子在眼科领域的应用提供思路。

表皮生长因子（epidermal growth factor，EGF）;成纤维细胞生长因子（fibroblast growth factor，FGF）;血管内皮生长因子（vascular endothelial growth factor，VEGF）;神经生长因子（nerve growth factor，NGF）;血小板衍生生长因子（platelet derived growth factor，PDGF）;胰岛素样生长因子（insulin-like growth factor，IGF）;转化生长因子 （transforming growth factors，TGF）;肿瘤坏死因子（tumor necrosis factor，TNF）;FGF受体（FGF receptor，FGFR）;EGF受体（EGF receptor，EGFR）;视网膜神经节细胞（retinal ganglion cell，RGC）;肝细胞生长因子（hepatocyte growth factor，HGF）;磷脂酰肌醇3激酶（phosphoinositide 3-kinase，PI3K）;蛋白激酶B（protein kinase B，AKT）;胞外信号调节激酶（extracellular signal-regulated kinase，ERK）;信号转导及转录激活因子（signal transduction and activator of transcription，STAT）;白介素（interleukin，IL）;基质金属蛋白酶（matrix metalloproteinase，MMP）;准分子激光原地角膜消除术（Laser-assisted keratomileusis，LASIK）;

眼的发育是一个复杂且高度受控的过程。脊椎动物的眼睛由多种组织组成，这些组织在胚胎时期起源于表面外胚层、神经外胚层、神经嵴和中胚层的间充质 [1] 。眼的发育过程中，不同类型的细胞在遗传基因和生长因子的共同调控下，实现有序分化和排列 [ 2- 4] 。眼睛是发育过程中容易发生畸变的器官之一。各种遗传性眼部疾病的发病率已经达到2%；近视、斜视、散光等在我国青年中的发病率已经达到50%左右；60岁以上人群眼睛的老视、白内障发生率接近80%；糖尿病性视网膜病变已成为四大主要致盲疾病之一 [5] 。尽管临床上已经有针对白内障、青光眼、糖尿病视网膜病变等眼部疾病的治疗手段或治疗药物，但诸如视网膜黄斑水肿、严重的视神经损伤、遗传因素引起的干眼等眼部疾病仍然缺乏令人满意的治疗方法或治疗药物。

生长因子在细胞和分子水平上控制眼形态的发生 [ 6- 7] 。了解受生长因子调节的组织相互作用有助于阐明眼正常和异常发育的生理、病理机制。最近研究报道表明，EGF表达量异常会导致多种眼前节发育缺陷 [8] 。FGF10在兔干眼模型中可以增加泪河高度和泪河面积，促进角膜上皮愈合，减少角膜和结膜上皮细胞的凋亡并增加黏蛋白Muc1的产生 [9] 。VEGF是一种血管通透性因子，可诱导新生血管形成，是参与视网膜新生血管形成的最主要因素 [ 10- 11] 。生长因子在眼部疾病调控作用的研究推动了生长因子及其抗体药物的研发，EGF滴眼液、碱性FGF滴眼液、NGF滴眼液已应用于临床角膜损伤治疗 [ 12- 15] 。以VEGF为靶点的抗血管形成药物已经成为年龄相关性黄斑变性的临床一线用药 [16] 。

发育过程及正常眼组织中生长因子及其受体表达异常将导致眼部疾病的发生，了解生长因子在眼的发育和眼部疾病调控中的作用对于眼部疾病的诊断及眼科药物的开发具有重要意义。本文综述了生长因子在眼的发育和眼部疾病调控中的研究进展，旨在为生长因子应用于眼科疾病的诊断和治疗提供依据。

生长因子与眼的发育

生长因子在胚胎发育过程中起到营养物质的作用，作为信使可调控细胞的迁移、增殖和分化。目前，已知包括FGF、EGF、NGF、PDGF、IGF、TGF、中胚层生长因子、TNF、血小板活化因子、睫状神经营养因子以及血管生成和抗血管生成的各种生长因子等参与眼发育的调控。以下介绍几种在眼的发育及维持眼正常功能中起重要作用的生长因子。

FGF

FGF在胚胎发育、血管生成、伤口愈合及多种组织和细胞的增殖与分化中起到关键作用 [ 17- 19] 。FGF与眼部各组织的发育及分化密切相关，包括角膜 [20] 、视网膜 [21] 、晶状体 [22] 等。在眼发育早期，FGF1和FGF2介导视泡的神经上皮分裂为神经视网膜和视网膜色素上皮结构域 [21] ，并对视杯祖细胞的增殖、神经视网膜细胞分化的增强和视网膜色素上皮细胞分化的抑制起到至关重要的作用 [23] 。小鼠中枢神经视网膜的 FGFR1和 FGFR2被有条件敲除后，视杯在FGF信号缺陷区域异位形成视网膜色素上皮样结构 [24] 。FGF信号也与睫状缘的发育有关，发育中周围视网膜的FGF信号缺失会破坏睫状体边缘的发育并导致无虹膜 [25] ，如FGF9的结构性缺失会影响睫状体边缘区的发育 [26] 。在晶状体发育过程中，FGF1和FGF2在晶状体上皮细胞的增殖、移行和分化过程中起重要的作用 [ 27- 28] 。其中，FGF2是晶状体胚胎发育的必需因子，能与Wnt信号转导通路协助促进晶状体的胚胎发育 [29] 。FGF2能促使G0和G1期晶状体上皮细胞进入分裂前感受态 [30] ，在低、中浓度时可促进大鼠原代晶状体上皮细胞增殖和迁移，在高浓度时促进纤维分化 [31] ，并可在骨形成蛋白的协同下进一步刺激晶状体次级纤维细胞分化 [32] 。此外，FGF10是人类泪腺和小鼠哈德氏腺发育所必需的 [33] 。FGF10从眼周间质分泌，并与其在表面外胚层上的受体FGFR2Ⅲb结合，以诱导泪腺萌芽；FGF10-FGFR2Ⅲb信号异常将导致泪腺发育异常 [34] 。因此，深入研究FGF对重要眼组织发育的调控，有利于为眼部疾病的防治提供新的思路和靶点。

EGF

EGF是最早发现的生长因子，通过与细胞表面的EGFR结合，激发受体酪氨酸激酶的活性，从而启动信号转导的级联反应，维持上皮细胞的正常新陈代谢。EGF在人体各种组织和体液中均可检测到，在眼部也广泛表达 [35] 。作为一种上皮细胞促生长因子，EGF作用的位点多为上皮细胞层 [36] 。成年小鼠角膜缘处的EGFR表达量高于角膜中央，提示EGFR高表达能使角膜缘干细胞保持未分化状态 [37] 。EGF通过影响视网膜和巩膜间的信号通路参与近视巩膜重塑 [38] 。郑瑾等 [39] 用一定浓度的EGF体外培养大鼠巩膜成纤维细胞，发现EGF对巩膜成纤维细胞的增殖有一定的促进作用。以上研究提示EGF是维持眼正常功能的重要生长因子之一。

NGF

NGF具有维持感觉神经元的存活、促进神经纤维的生长、增加感觉神经肽基因表达的作用，是较早发现的神经营养因子家族成员之一 [40] 。正常人的眼表上皮细胞可合成并分泌NGF，且NGF在角膜、结膜、泪囊、泪腺等中均有表达，参与调控眼表功能反应 [41] 。NGF对眼表具有多向调节作用，如调节免疫反应、调节角膜结膜上皮细胞增殖和杯状细胞黏蛋白的分化 [42] 。NGF在视觉系统的发育过程中高表达，影响神经元的增生、存活以及选择性的凋亡 [43] 。在形觉剥夺性近视豚鼠模型中，随着形觉剥夺时间的延长，视网膜中NGF蛋白及mRNA表达减少，推测NGF参与介导视网膜细胞的生长发育和视网膜细胞内的信息调控，促进功能性视网膜发育期的分化 [44] 。因此，以NGF为靶点，治疗视网膜色素变性等所致视神经萎缩、缺血性视神经病变、神经营养性角膜炎等视觉系统疾病已受到业界的关注。

PDGF

PDGF是由两条多肽链通过二硫键连接而成的同源或异源二聚体，包括PDGF-AA、PDGF-BB、PDGF-AB、PDGF-CC以及PDGF-DD [45] 。PDGF与眼的发育过程密切相关。PDGF-AA在小鼠的晶状体或视网膜神经节细胞中特异性表达并促进星形胶质细胞增殖 [46] 。PDGF-BB保守基序基因缺失的转基因小鼠不仅表现出周细胞丢失和异常的脉管系统 [47] ，而且还会出现光感受器变性 [48] 。PDGF-BB过度表达可导致小鼠视网膜异常，如在Anestin增强剂下过表达PDGF-BB的转基因小鼠显示出视网膜缺陷，包括无组织的核层、光感受器变性和血管系统改变 [49] 。在髓鞘碱性蛋白特异性PDGF-BB表达转基因小鼠中也观察到视网膜折叠和视网膜毛细血管的解体 [50] 。因此PDGF-BB在视网膜发育中起重要作用。PDGF-CC在视网膜维护中同样具有重要性。功能获得和功能丧失试验均表明PDGF-CC通过PDGF受体-α和PDGF受体-β保护RGC [51] 。PDGF-CC可改善光感受器变性但不诱导小鼠视网膜血管生成 [52] 。PDGF-DD可促进各种眼细胞如视网膜血管周细胞、脉络膜成纤维细胞和视网膜衍生的血管内皮细胞的增殖、存活和迁移 [53] 。总之，PDGF参与调控多种眼组织的发育过程，在眼发育过程中扮演重要作用。

VEGF

VEGF是血管内皮细胞特异性的肝素结合生长因子，是一种血管生成有丝分裂原，在眼部主要分布于视网膜周细胞、血管内皮细胞和色素上皮细胞等。VEGF通过结合内皮细胞上存在的酪氨酸激酶受体发挥其特有的分子作用，能促进血管内皮细胞分裂、增殖、迁移以及促进细胞外基质变性、增加血管通透性 [54] 。VEGF在人类中主要存在五个亚型，分别为VEGFA、VEGFB、VEGFC、VEGFD和胎盘生长因子，其中VEGFA在正常眼脉管系统和新生血管组织中表达最丰富 [55] ，胎盘生长因子在视网膜浅表血管系统的动脉内皮细胞和生长的毛细血管芽中表达最明显 [56] 。研究显示，VEGF和胎盘生长因子与视网膜的发育息息相关且在血管形成方面有着协同作用，其中VEGF促使内皮细胞增殖并形成管状结构，而胎盘生长因子主要调节血管的生长和成熟 [ 57- 58] ｡

HGF

HGF是一种可调节多种细胞生长、运动和形态发生的多功能因子，可作用于肝细胞、上皮细胞、造血细胞、血管内皮细胞等多种细胞 [59] 。在眼部，HGF可由成纤维细胞、血管平滑肌细胞、角膜上皮细胞、晶状体上皮细胞、虹膜及视网膜色素上皮细胞、小梁细胞等产生 [60] 。HGF受体激活PI3K-AKT及ERK激酶信号 [61] ，促进细胞分裂、调控细胞周期作用及修复角膜上皮；同时HGF具有抑制成纤维细胞生成和抗纤维化作用 [62] 。此外，HGF在角膜损伤修复、维持角膜内皮完整性、调节晶状体上皮细胞功能等方面起着重要作用 [63] 。研究显示，HGF的水平和角膜病的易感性相关 [64] 。HGF通过维持ZO-1（角膜上皮紧密连接的标志物）的正常表达和分布，保护人角膜上皮细胞间的屏障；HGF还可以抑制细胞骨架蛋白质F-actin的重构，增强其对于角膜上皮屏障的保护作用 [65] 。HGF还可调节小梁细胞的生长和代谢 [66] ，增强内皮细胞中的基质金属蛋白酶活性进而影响葡萄膜巩膜外引流和眼压 [67] 。总之，HGF在维持眼组织稳态中发挥重要作用。

生长因子与眼部疾病的调控

在正常的生理条件下，各种生长因子处于动态平衡状态，如果受到干扰，会导致眼部疾病的发生。研究生长因子与眼部疾病的关系不仅能了解人类眼部疾病的发病机制，也可用于开发新的有效治疗方法。

角膜疾病

角膜所处的解剖位置特殊，容易受到创伤和感染等各种外界因素的刺激。各种生长因子在角膜伤口的愈合方面起到了重要作用。EGF、FGF和TGF-β能在体外刺激人和牛角膜上皮细胞、成纤维细胞及内皮细胞的趋化迁移 [68] 。FGF10可激活角膜上皮干细胞，使其不断增殖分化，从而促进角膜上皮损伤的愈合，并在兔角膜碱烧伤模型中得到证实 [69] 。FGF10还可以通过减轻角膜激光烧伤后的各种炎症反应加速角膜上皮细胞的增殖和迁移，促进角膜基质纤维增生，加快激光烧伤后受损角膜的修复等 [70] 。EGF对角膜的主要作用包括加速角膜上皮细胞增殖、促进角膜基质层胶原合成及促进内皮细胞的增殖；EGF还具有逆转糖皮质激素抑制上皮细胞增殖和延缓创口修复的作用 [71] 。在一项比较研究中，EGF和FGF2均可促进角膜上皮细胞的增殖，FGF2作用更强，而长期使用EGF在促进角膜愈合过程中可减少基质新血管生成 [72] 。TGF-β的主要作用是加快炎症反应及刺激细胞外基质合成和不断沉积，进而加速角膜基底膜和基质的重构和修复，促进角膜伤口愈合，但后期的过度表达可导致细胞外基质合成及降解失衡，从而造成组织纤维化 [73] 。以上研究结果提示，生长因子参与角膜相关疾病的发生和发展，为角膜疾病的治疗提供了重要的研究方向。

角膜新生血管是多种眼表疾病如感染性角膜疾病、眼化学伤、热烧伤、非感染性角膜疾病角膜变性的显著特征之一，不但严重影响视力，也是角膜移植排斥反应发生的高危因素。角膜新生血管的形成与多种生长因子的调控密切相关，生长因子之间的平衡是保持角膜透明的重要条件 [74] 。生理状态下，血管生成抑制因子与血管生成促进因子的表达处于动态平衡，因此角膜中不会有新生血管形成 [75] 。但创伤、低氧、感染或免疫复合物的沉积会打破生长因子之间的平衡，从而引发角膜新生血管 [76] 。

视网膜疾病

视网膜疾病在临床上主要分为五种：视网膜血管性疾病、视网膜炎症疾病、视网膜脱离、视网膜变性和视网膜肿瘤，以糖尿病视网膜病变和视网膜静脉阻塞为代表的血管性病变最为常见。

VEGF是一种血管通透性因子，可诱导新生血管形成，是参与视网膜新生血管形成的最主要因素 [ 10- 11] 。VEGF通过蛋白激酶C介导的闭锁蛋白磷酸化破坏血-视网膜屏障，蛋白激酶C通过内吞过程诱导紧密连接的解体从而导致血管渗漏，引起黄斑水肿 [77] 。VEGF可上调细胞内黏附分子-1，通过促进白细胞黏附和淤滞，导致毛细血管阻塞及无灌注区形成，引起组织缺血、缺氧；而缺氧又是VEGF的强效刺激因素，可使VEGF数倍上调，形成前馈循环，从而导致视网膜血管病变不断加重 [78] 。高糖状态下，氧化应激、缺氧和炎症反应等均能诱导VEGF表达增加，VEGF与血管内皮细胞上的VEGF受体结合可引起内皮细胞增殖、迁移，进一步诱导视网膜新生血管形成 [79] 。

IGF-1是VEGF的上游因子，IGF-1可以促进VEGF的表达，特别是血-视网膜屏障破坏后，IGF-1可能会加速糖尿病视网膜病变的进展；玻璃体腔注射抗IGF-1可能可以替代抗VEGF成为一种新的疗法 [80] 。

FGF2也是一种很强的促血管生成因子。Dong等 [81] 发现，FGF2可通过FGFR信号激活STAT3，以剂量依赖的方式促进激光诱导小鼠视网膜新生血管的形成。FGF2能促使内皮细胞在缺血缺氧环境下增多，也能促进体外培养的内皮细胞 [82] 和视网膜色素上皮细胞 [83] 的增殖，引起毛细血管狭窄和闭塞，加速糖尿病视网膜病变的病理损害。FGF2还可促使层粘连蛋白、纤维连接蛋白及Ⅳ型胶原生成增加，并使糖尿病视网膜病变患者玻璃体中内皮细胞分泌纤溶酶原激活物增加 [84] ，从而快速分解细胞基质和基底膜等大分子物质，并促使可形成毛细血管的细胞迅速穿过上述结构进行迁移和增殖，形成新生血管。

以上研究表明，多种生长因子介导了视网膜血管性疾病，是该类疾病治疗的重要靶点。

白内障和后发性白内障

白内障是指因老化、遗传、局部营养障碍、免疫与代谢异常、外伤、中毒、辐射等引起晶状体代谢紊乱，导致晶状体蛋白质变性而发生混浊。晶状体上皮细胞过度凋亡及晶状体蛋白损伤与房水内众多细胞因子含量的改变有关 [85] 。糖尿病性白内障患者术前房水中FGF2和IGF-1含量的增加可能与高糖状态晶状体上皮细胞受损、凋亡及血-房水屏障破坏有关，其水平差异反映了不同生长因子在不同发病阶段的作用 [86] 。糖尿病白内障患者房水中生长因子VEGF、TGF-β、血管内皮细胞黏附分子浓度变化与糖网增殖期变化具有一致性，且因子间存在相关性 [87] 。因此，白内障患者房水生长因子的浓度反映了不同生长因子在不同发病阶段的作用，可作为治疗和预后的参考指标。

后发性白内障指白内障摘除术后，或外伤性白内障部分皮质吸收后残留晶状体上皮细胞增殖、分化并移行导致的晶状体后囊膜混浊。EGF是促进白内障术后晶状体上皮细胞生长的重要因子。陶津华等 [88] 发现，EGF对人晶状体上皮细胞具有促进迁移的作用。Huang等 [89] 研究发现，EGFR的干扰小RNA能够阻断EGF-EGFR信号通路，使人晶状体上皮细胞生长周期阻滞于G1期，有效预防晶状体后囊膜混浊的发生。TGF-β1和TGF-β2均可由晶状体上皮细胞表达，活化的TGF-β水平在白内障术后显著升高；TGF-β可诱导晶状体上皮细胞发生上皮间质转换，并转分化为肌成纤维细胞，其形态学和生物学均与晶状体后囊膜混浊的形成类似 [90] 。白内障术后剩余的晶状体上皮细胞保留在前囊上，诱导HGF释放，激活其受体c-Met并诱导ERK和JNK/SAPK以及PI3K活化 [91] ，从而诱导细胞周期蛋白D1的表达，刺激晶状体上皮细胞增殖并造成晶状体后囊膜混浊。因此，EGF、TGF-β和HGF都是治疗晶状体后囊膜混浊的重要靶点。

视神经损伤

创伤、缺血、高眼压、药物中毒、代谢障碍等多种因素均可以造成视神经的不可逆损伤。神经营养因子能够促进神经元的存活和诱导轴突的生长，对中枢和外周神经系统的组织细胞均具有广泛的生物学活性 [92] 。神经营养因子的剥夺是视神经损伤后RGC凋亡的主要原因之一，给予外源性的神经营养因子能够促进视神经损伤后RGC的再生和发挥神经保护作用 [93] 。

最典型的神经营养因子是NGF。NGF具有维持感觉神经元存活、促进神经纤维生长、增加感觉神经肽基因表达的作用，是最早发现的神经营养素家族成员之一 [ 94- 95] 。NGF能降低兔高眼压后视网膜髓鞘碱性蛋白的含量，提高RGC的存活数，对RGC损伤后的修复有明显的促进作用 [96] 。实验证实，NGF可以促进脱髓鞘性视神经炎小鼠RGC的存活 [97] ，提高由青光眼、糖尿病视网膜病变引起的鼠RGC的存活率 [98] ，以及促进视神经挫伤后大鼠RGC的存活和轴突生长 [99] 。然而，有研究表明，NGF能通过调节VEGF促进淋巴管形成，可能作为致病因素在角膜伤口修复过程中对正常神经及淋巴血管重塑起负性调节作用 [100] 。

除了NGF以外，睫状神经营养因子、胶质细胞源性神经营养因子、色素上皮衍生因子、粒细胞集落刺激因子等神经营养因子也对视神经损伤有较好的修复作用。睫状神经营养因子可以通过PI3K/PIP3/AKT通路，激活mTOR及其下游信号促进视神经轴突生长 [101] 。胶质细胞源性神经营养因子能够提高视神经损伤后RGC的存活率，通过调节增强有效跨膜转运实现神经保护 [102] ；联合嗅神经鞘细胞移植能促进成年大鼠视神经损伤后功能恢复 [103] 。色素上皮衍生因子能够在视神经离断后减少神经节细胞凋亡，增加再生轴突数 [104] 。皮下注射粒细胞集落刺激因子能够产生剂量依赖性的视神经保护作用，且至少能在一定程度上独立于干细胞发挥治疗作用 [105] 。

此外，其他种类的生长因子如FGF1 [ 106- 107] 、FGF2 [ 108- 109] 和IGF [ 110- 111] 等也具有保护视神经的作用。

干眼

干眼症是指泪液的量或质的异常引起泪膜不稳定和眼表损害的多种病理状态的总称。虽然诱导干眼症的因素很多，但不同类型干眼症的发病机制较为相似。眼表的炎症反应是目前干眼症发病学说中被认同度较高的观点之一 [112] 。干眼会导致眼表面高渗，从而引发炎症介质的释放，上调MMP-3、MMP-9、TNF-α、IL-1β等表达 [ 113- 114] 。

EGF主要参与泪液的产生，为泪液中有效的蛋白成分。EGF是泪液神经调节通路的重要因素之一，若阻断EGFR系统可能导致干眼发生 [115] 。杨春等 [116] 检测干眼症患者的泪液发现EGF含量明显下降，而泪液分泌不足会导致EGF含量进一步下降，加重疾病进程，因此EGF可以作为干眼检测的可靠指标。

此外，TGF-β1可通过下游信号分子磷酸化Smad2/3与Smad4复合物限制结膜内杯状细胞增殖 [117] ，可能与干眼形成有关。NGF异常表达直接参与了干眼局部炎症反应 [118] 。干燥综合征患者眼部慢性炎症反应与NGF-β/TrkA异常表达有关，其损伤机制主要为影响EGFR/MEK/ERK信号转导系统激活 [119] 。还有研究发现，IGF-1能有效加速LASIK术后角膜表面超微结构及神经再生的修复，并可缓解干眼症状 [120] 。

以上研究表明，深入了解不同生长因子在干眼调控中的作用及其分子机制，有利于针对不同类型干眼开展对因治疗。

近视

近视是患病率最高的眼科疾病之一，生长因子与眼球发育和近视发病密切相关，FGF、EGF、TGF、IGF等具有影响巩膜厚度变化和调控近视发生发展等功能 [121] 。

FGF-2还能通过促进多巴胺的合成来抑制形觉剥夺性近视轴的拉长，从而拮抗形觉剥夺性近视的发生和发展 [ 122- 123] ；也可与TGF共同影响MMP的表达来调控细胞外基质，进而参与近视的发展 [124] 。同时，也有研究认为， FGF10基因rs399501位点与超高度近视相关 [125] 。

EGF参与了近视巩膜重塑。Barathi等 [126] 发现阿托品抗近视效应可能是由于EGFR激活ERK-MAPK信号通路，调节巩膜成纤维细胞的增殖和分化，进而影响巩膜重塑。

TGF-β与近视密切相关，能影响高度近视眼巩膜扩张中细胞的增殖、分化和迁移 [43] 。在形觉剥夺性近视动物模型中，TGF-β含量降低，促进MMP降解细胞外基质中胶原和蛋白多糖，使得巩膜变薄，最终导致高度近视的发生 [ 127- 128] ；同时TGF-β也可通过增强巩膜收缩来诱发近视 [129] 。最新研究显示，在视网膜色素上皮细胞中，TGF-β2、TGF-β3等近视相关因子水平可能因转录因子HOXA9介导升高而促进近视的发展 [130] 。

IGF-1基因与高度近视显著相关 [131] ，其能通过引起巩膜组织MMP和金属蛋白酶组织抑制物表达失衡，提高MMP活性，减少巩膜成纤维细胞生长与细胞外基质的合成，导致巩膜重塑变薄、眼轴延长而出现高度近视 [26] 。

结语

尽管国内外学者对生长因子参与眼部疾病的发生过程形成了一定认识，但生长因子及其受体如何诱发或治疗眼部疾病的机制仍有许多未解之谜。眼发育过程中各组织相互作用，整个过程可能需要几个生长因子的协同作用。如在晶状体的发育过程中，FGF、IGF-1、PDGF、EGF、TGF-α和HGF等因子在上皮细胞增殖过程中均有促进作用。目前认为FGF是促使G0和G1期上皮细胞进入分裂前感受态的启动因子，而IGF-1则推动感受态细胞通过限制点进入S期，完成染色体DNA和相关蛋白质的合成，两者在上皮细胞增殖过程中起协同作用 [30] 。Chen等 [132] 研究发现，EGF和HGF受体通过蛋白激酶C活化和ERK磷酸化两条途径诱导视网膜色素上皮细胞迁移，并且这两种生长因子不仅可以被相应自身配体激活，而且可以被异源配体交叉激活，从而增强信号转导和细胞迁移。因此，进一步揭示生长因子与眼部疾病发生发展的分子机制，将极大推动以生长因子及其受体为靶点的眼部疾病治疗药物的开发，提高眼部难治性疾病的诊疗水平。

COMPETING INTERESTS

所有作者均声明不存在利益冲突

Funding Statement

浙江省“尖兵”“领雁”研发攻关计划（2022C03110）

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