血清FGF2与糖尿病视网膜病变的研究进展
Advances in the Study of Serum FGF2 and Diabetic Retinopathy
摘要: 糖尿病视网膜病变(Diabetic Retinopathy, DR)作为糖尿病最严重的慢性并发症之一,其所致的糖尿病性黄斑水肿(Diabetic Macular Edema, DME)已成为成年人视力丧失的主要原因。当前研究表明,血管内皮生长因子(Vascular Endothelial Growth Factor, VEGF)主导的促血管生成通路在DME发病中起核心作用,但临床抗VEGF治疗存在30%左右的无应答率,表明需深入探索其他致病因子的协同作用。成纤维细胞生长因子2 (Fibroblast Growth Factor-2, FGF2)作为最早发现的促血管生成因子,既往研究揭示其在DME病理进程中具有重要潜在价值。本文系统综述FGF2的生物学特性、与VEGF的协同作用机制、在DR进展中的临床相关性及靶向治疗前景,为DME的精准诊疗提供新思路。
Abstract: Diabetic retinopathy (DR), one of the most serious chronic complications of diabetes mellitus, and its resultant diabetic macular edema (DME) have become the leading cause of vision loss in adults. Current studies suggest that the pro-angiogenic pathway dominated by Vascular Endothelial Growth Factor (VEGF) plays a crucial role in the pathogenesis of DME, but clinical anti-VEGF therapy has a non-response rate of about 30%, suggesting that the synergistic effects of other pathogenic factors need to be explored in depth. Fibroblast Growth Factor-2 (FGF2), as the earliest identified pro-angiogenic factor, has been revealed in previous studies to be potentially valuable in the pathologic process of DME. This paper systematically reviews the biological properties of FGF2, its synergistic mechanism with VEGF, its clinical relevance in the progression of DR, and the prospect of targeted therapy, which will provide new ideas for the precise diagnosis and treatment of DME.
文章引用:朱和林, 蒋雨. 血清FGF2与糖尿病视网膜病变的研究进展[J]. 临床医学进展, 2025, 15(7): 1486-1495. https://doi.org/10.12677/acm.2025.1572152

1. 引言

糖尿病(Diabetes Mellitus, DM)是一种慢性代谢性疾病,其特征是由于胰岛素分泌绝对或相对不足导致的持续高血糖。糖尿病主要分为1型和2型:1型糖尿病(Type 1 Diabetes Mellitus, T1DM)是由于自身免疫反应导致胰腺中分泌胰岛素的细胞受损,造成胰岛素绝对缺乏。2型糖尿病(Type 2 Diabetes Mellitus, T2DM)为最多发的糖尿病种,它是由胰岛素抵抗和分泌不足导致胰岛素相对缺乏。国际糖尿病联合会(International Diabetes Federation, IDF)统计全球20~79岁人群中,2021年患有糖尿病的人数为5.37亿,2030年估计为6.43亿,而到2045年预计上升到7.83亿。在中国形势更加严峻,根据IDF数据统计,截止2021年,我国20~79岁人群中患糖尿病的数量超过1.4亿,高居世界首位[1]。随着降糖药物的不断改革更新,高水平的血糖及危重的糖尿病急性并发症已经能得到较好的控制。然而积极控糖也不能阻止糖尿病慢性并发症的发生,而这些非急症的并发症往往会导致糖尿病患者残疾甚至死亡的结局,加重公共卫生负担。

糖尿病视网膜病变(Diabetic Retinopathy, DR)作为糖尿病主要的慢性并发症之一,是导致视力丧失的重要病因,也是导致失明的重要原因。目前认为DR的发生与血管生成、氧化应激和炎症反应等相关[2] [3]。黄斑区是视网膜中感受光刺激最敏感的区域,如果这个区域发生病变,将影响光感受器的接触及其对光的敏感性。糖尿病性黄斑水肿(Diabetic Macular Edema, DME)就是黄斑区发生渗出性水肿的病变,它属于DR的并发症,可在DR的任何阶段发生,研究表明DME的发病率随着病程的延长和DR阶段进展而增加。在所有的糖尿病眼部并发症中,DME是引起视力损害甚至失明的主要原因,其发病率在世界范围内逐年增加[4]。国外有研究表明,I型糖尿病和II型糖尿病在十年内发生DME的概率分别为20.1%和25.4% [5]。由于DME的严重致盲性,及时有效防控DME对于阻止视力出现不可逆损害至关重要。

DME的发病机制是多因素且复杂的,目前认为主要是持续的高血糖诱导糖基化终末产物(Advanced Glycosylation End Products, AGEs)产生和缺氧引起氧化应激等多种代谢异常导致促血管生成因子分泌引起视网膜新生血管(Retinal Neovascularization, RNV)生成及毛细血管壁通透性增加,从而进一步引起毛细血管血–视网膜屏障(Blood-Retinal Barrier, BRB)的破坏。由于BRB的大范围破坏而导致毛细血管内大量液体渗出到视网膜引起视网膜的弥漫性水肿从而形成黄斑水肿。大量研究发现DME发生发展中最重要的促血管生成因子是血管内皮生长因子(Vascular Endothelial Growth Factor, VEGF),VEGF主要是通过增加毛细血管通透性及促进新生血管生成引起BRB的破坏在DME的发病中起着关键作用[6]

VEGF是一种促进血管内皮细胞增殖、分化、驱化和改变血管内皮致密性的特异性细胞因子,属于肝素结合生长因子。VEGF发挥促血管内皮生长作用主要是通过结合分布在内皮细胞上的酪氨酸激酶受体来实现的[7]。在过去10余年中,国内外大量研究探究并证实了VEGF与DME的密切联系,研究发现DME患者的VEGF水平比起健康人群和单纯糖尿病患者显著升高,并且与DME的严重程度相关[8],以VEGF为作用靶点的治疗已作为一线治疗方案广泛应用于临床。而仅以VEGF作为DME治疗靶点的临床有效应答率只有70% [8],表明DEM的发生涉及除VEGF之外的相关因子,因此其他作用靶点亟待研究开发。

成纤维细胞生长因子2 (Fibroblast Growth Factor-2, FGF2)也叫碱性成纤维细胞生长因子(Basic Fibroblast Growth Factor, bFGF),是一种促有丝分裂生长因子,作为最早被研究报道的促血管生长因子,其在病理性血管生成中的作用被广泛研究。通过对病理性血管内皮刺激发挥诱导其增殖和分化的作用,直接促进新生血管的生成。此外,FGF2还能通过上调VEGF的表达来实现间接促进血管生成的作用[9]-[11]。FGF2通过其与四种受体亚型成纤维细胞生长因子受体(Fibroblast Growth Factor Receptor, FGFR) FGFR1、FGFR2、FGFR3和FGFR4的相互作用来发挥生物学性能[12],在许多疾病中发挥着重要作用。

DME是糖尿病眼部并发症中对视力损害威胁最大的并发症[13],因此积极探究其发病机制尤为重要。DME发病的关键为新生血管的生成,VEGF和FGF2都属于参与血管生成的基本调节因子,国内外大量研究表明二者在促进新生血管形成上具有协同作用[14] [15]。本文将对FGF2、VEGF与DR、DME之间的相互关系进行详细的综述,以期对DR的早期诊断与治疗提供新的临床思路与依据。

2. DME的发病机制

在DR中,严重影响视力的两个重要原因为增殖性糖尿病性视网膜病变(Proliferative Diabetic Retinopathy, PDR)和DME。DME是一种由缺氧、血管生成、高通透性和炎症等多种因素共同作用的复杂疾病,它的发病机制复杂,尚未完全阐明。DME的特征临床表现为视网膜内液体(Intraretinal Fluid, IRF)和视网膜下液体(Subretinal Fluid, SRF)渗出后造成黄斑区弥漫性水肿,其出现是新生血管生成、BRB完整性破坏、视网膜周细胞(Peripapillary Retinal Cells, PRC)、内皮细胞(Endothelial Cell, EC)紧密性损害等引起视网膜毛细血管通透性增高从而渗漏的结果。

视网膜微血管EC和视网膜色素上皮细胞(Retinal Pigment Epithelial Cells, RPE)分别构成了BRB的内部和外部屏障。生理状态下,视网膜中液体的流入和流出的平衡由BRB的完整性以及Müller胶质细胞(Müller神经胶质细胞是视网膜特有的主要大胶质细胞)和IRF的主动引流功能维持,使视网膜保持在相对脱水的条件下并保持正常功能[8]。长期葡萄糖的过量堆积激活蛋白激酶C (Protein Kinase C, PKC)、AGEs的积累、多元醇途径、和氨基己糖生物合成途径等病理生理反应而逐步对机体产生负面影响。AGEs是指一组分子结构异常的终末产物,是还原糖的醛基与氨基酸、蛋白质和脂类等大分子物质的游离氨基之间通过缩合、氧化修饰后形成的化合物[16]。有研究表明这类化合物和DR有密切关联,是检测早期DR和预测进展的潜在生物标志物[17]。这种化合物进一步引起血流紊乱和血管细胞(包括PRC和EC)功能降低或消失,继而引发视网膜毛细血管缺血缺氧。作为对局部缺氧的反应,缺氧诱导因子-1 (Hypoxia-Inducible Factor-1, HIF-1)途径被激活,进一步诱导VEGF等血管生成刺激物过度表达[18],从而刺激RNV生成以改善视网膜组织的氧合,这种新生血管由于结构缺陷及血管壁的不完整进一步加重视网膜细胞缺血缺氧[19] [20]。VEGF升高引起组成血管壁EC紧密连接的膜蛋白的结构破坏从而导致渗漏。此外,VEGF还会通过促进丝裂原活化蛋白(Mitogen-Activated Protein, MAP)的活性导致EC的过度增殖。以上两种现象都会导致视网膜毛细血管壁的通透性升高和BRB受损,从而出现黄斑区IRF或SRF的异常积聚形成肿胀导致黄斑水肿[6] [18]。目前认为慢性高血糖导致的RNV生成、BRB受损及视网膜毛细血管壁通透性增加是PDR、DME发生的重要因素。

此外,有研究表明许多炎症相关因子如白介素-6 (Interleukin-6, IL-6)、白介素-1β (Interleukin-1β, IL-1β)、白介素-8 (Interleukin-8, IL-8)、肿瘤坏死因子α (Tumor Necrosis Factor-α, TNF-α)、肝细胞生长因子(Hepatocyte Growth Factor, HGF)、胰岛素样生长因子-1 (Insulin-like Growth Factor-1, IGF-1)等也会引起BRB受损从而导致黄斑水肿,与DME的存在和严重程度相关[18] [21]。有研究发现星形胶质细胞、Müller细胞功能障碍和丢失也与DME相关[22] [23]

由此可见,DME起病的关键主要归因于VEGF由缺氧刺激诱导其表达上调,从而导致新生血管生成、BRB受损及视网膜毛细血管通透性升高,目前认为其在DME的发生发展中至关重要。研究发现,VEGF能促进血管内皮增殖分化,促进血管生成,同时增加血管通透性,使血管内成份渗漏,继而促进新生血管的形成[6]

尽管VEGF在DME的发生发展中起主要作用,在过去十年玻璃体内抗VEGF被认为是DME的治疗金标准(VEGF抑制剂通过阻断VEGF来抑制新生血管生长、改善视网膜毛细血管的渗出积聚),但其他致病因素也有助于新生血管生成、BRB的破坏和血管通透性的增加,因此靶向VEGF并不能抑制DME中涉及的所有因素。有研究表明超过三分之一的患者即使在每周注射多达4次的情况下对抗VEGF治疗没有足够的反应,亟待寻找新的治疗靶点从而实现个体化治疗[24]

3. VEGF和FGF2的生物学特性

VEGF是一种分泌型二聚体糖蛋白,在眼部主要分布在PRC、RPE、EC等处,并由视网膜中的PRE,PRC,EC,神经胶质细胞,müller细胞和神经节细胞等多类细胞合成和分泌,而视网膜中分泌VEGF的主要来源是müller细胞和PRE,血管EC是其发挥生物学作用的主要靶点[25]。VEGF家族包含六大成员:VEGF-A、B、C、D、E、F和胎盘生长因子(Placenta Growth Factor, PIGF) 1、2,因为VEGF-E(病毒VEGF,存在于副痘病毒1中)、VEGF-F(蛇毒VEGF)都不是内源性人类分子,所以对其研究较少,主要集中于VEGF-A、B、C、D这四种上[26]。VEGF发挥生物学效应主要是通过刺激其细胞表面的血管内皮生长因子受体(Vascular Endothelial Growth Factor Receptors, VEGFR)来实现,目前发现其存在VEGFR-1、VEGFR-2、VEGFR-3三类受体。这些受体属于酪氨酸激酶家族中的血小板源性生长因子受体,其中VEGFR-2的表达主要在内皮细胞上,并且认为其是发挥促有丝分裂、促血管生成和促进血管通透性等病理生理作用的主要生物学效应受体[6] [27]

VEGF各个成员的生理特性不同,VEGF-A主要通过刺激血管EC增殖、分裂和迁移对血管内皮产生作用,VEGF-B主要是通过拮抗氧化应激抑制病理性新生血管生成,而VEGF-C和VEGF-D主要对淋巴系统发挥作用[21]。PlGF也被归为VEGF家族的成员,被VEGFR-1结合[28]。PlGF包括PlGF-1和PlGF-2两种异构体,其同样在缺血缺氧刺激下促进病理性血管生成,并且这个过程是不依赖VEGF的[27] [28]。VEGF-A是VEGF途径中所有分子促血管生成反应的主要介质,在人体内以16种亚型存在,其中最为人所知的是VEGF-A165 [29]

几种视网膜细胞,以PRC、RPE细胞、血管EC、神经元细胞和星形胶质细胞的方式,都可以产生VEGF-A [30]。高糖状态下,低氧、氧化应激和炎症相关因子都可以通过HIF-1途径而引起VEGF的表达上调[31]。VEGF-A除了可以RNV生成外,还通过破坏血管EC之间紧密连接而导致血管通透性增加,从而导致DME的发生[27] [32] [33]

此外VEGF的过度表达还可以通过巨噬细胞的迁移而诱导血管重构,导致血管进一步异常[34] [35]。目前抗VEGF治疗主要是靶向拮抗一种或多种VEGF亚型(主要是VEGF-A和/或PIGF)、VEGF受体或信号通路,来维持BRB的完整性。抗VEGF药根据分子模式分为寡核苷酸适配体、单克隆抗体和受体融合蛋白,目前广泛应用于临床的后两类。单克隆抗体是指通过抗VEGF抗体或抗体片段如(贝伐珠单抗、雷尼珠单抗),受体融合蛋白则是指融合了多种VEGF及片段的融合蛋白直接与VEGF结合从而影响VEGF抗体与VEGF的结合过程(如阿柏西普、康柏西普),近年来人VEGF-A单链抗体片段抑制剂布洛塞珠单抗、促血管生成素2和VEGF的双特异性抗体法瑞西单抗作为新药也逐步应用于临床[36]-[38]

FGF2也叫做bFGF,是FGFs家族中研究最多、最典型的一类多肽[39],被发现在机体内许多系统中具有生物学活性,参与了许多疾病的发生。大脑、视网膜、肾上腺、胎盘及卵巢等血管丰富的组织中都有FGF2的分布[40]。研究表明,血管EC是FGF2的合成细胞,同时也是其发挥生物学效应的主要受体。FGF2对EC的增殖分裂、迁移分化等起重要作用。诸多研究发现FGF2在促血管生成、增加血管通透性、组织再生修复等方面起重要的作用[41]。临床研究发现FGF2可促进角膜细胞的增殖、分化从而促进角膜的修复,临床上已有重组牛碱性FGF滴眼液应用于角膜上皮细胞受损所致的相关疾病[42] [43]

FGF2亚型缺乏分泌的前导序列,并通过替代分泌途径、膜囊泡脱落或细胞损伤后以有限的量释放[44]。通常,FGF2对EC产生的生物学效应是旁分泌刺激的结果,此外,由于自身产生FGF2,EC可以经历自分泌或内分泌刺激。由此可见,EC自身产生的内源性FGF2可能通过发挥自分泌、内分泌或旁分泌作用从而在EC中诱导促血管生成状态,为血管生长创造有利的环境,在血管生成和血管病变的发病机制中发挥重要的作用[45] [46]。FGF2以低分子量异构体(Low Molecular Weight, LMw)和高分子量异构体(High Molecular Weight, HMw)两种形式存在,LMWFGF2是一个18 kDa的蛋白质,主要存在于细胞质和细胞核中,也可以由靶细胞分泌,LMW FGF2与细胞表面硫酸肝素蛋白聚糖(Recombinant Heparan Sulfate Proteoglycan, HSPG)和FGFR相互作用,形成一个由FGF2、FGFR和HSPG组成的三元复合体从而启动信号通路,从而进一步激活包括Ras、Raf、丝裂原活化蛋白激酶(Mitogen-Activated Protein Kinase, MAPK)和细胞外调节蛋白激酶(Extracellular Regulated protein Kinase, ERK)等多条下游信号通路;HMw FGF2包括22-、22.5-、24-和34-kDa多种亚型,其信号传导通常不依赖于FGFRs而主要分布于细胞核[47]。目前发现FGF2可由视网膜多种类型的细胞分泌,包括PRE、EC、Miiller细胞、视杆细胞、视锥细胞等。FGF2通过与HSPGs作为辅因子结合并激活FGFRs后使FGFR发生二聚化,继而使其介导的蛋白激酶结构域上的氨基酸残基磷酸化来发挥其在靶细胞的生物学反应[39]。目前已分离出四种高亲和力的酪氨酸激酶(Tyrosine Kinase, TK) FGFR, FGFRl~FGFR4。通过两种特异性的衔接蛋白即成纤维细胞生长因子受体底物(Fibroblast-growth-factor Receptor Substrate 2, FRS2)和磷脂酶C (Phospholipase Cγ, PLCγ)激活胞内的信号通路,FRS2进而激活Sos-Grb2-Ras/MAPK (Son of sevenless, Sos; Growth factor receptor-bound protein 2, Grb2)信号通路,PLCγ激活PKC-PKB/AKT信号通路从而发挥生理作用[39] [48]。Dong Z等学者通过研究发现,FGF-FGFR信号转导体通过激活STAT3调节途径致病性血管生成[49]。研究发现炎症及炎症相关因子以及一氧化氮(Nitric Oxide, NO)能够促进FGF2的表达增加,从而维持及增强其功能,同时发现FGF2可通过炎症细胞因子对炎症细胞的募集起到协同作用从而扩大炎症反应[50]。FGF2不仅可以通过增加NO的表达而促进血管尤其是动脉的生成,还可以通过促进VEGF及蛋白水解酶的表达增加血管通透性[51]

4. VEGF和FGF2与DME

DME发生发展的关键环节是促血管生成因子促进新生血管生成及血管通透性增加,而VEGF和FGF2是被分离出来的最关键的促血管生成因子。血管形成是以血管扩张和结构改变起始的,具体是由病变组织分泌的促血管生成的细胞因子(包括VEGF、FGF2、NO、AII-2等)刺激血管EC和壁细胞发生功能及形态改变,这个过程主要是通过旁分泌和自分泌途径完成[14] [52]。血管的形成主要是指毛细血管和小动脉的形成,VEGF主要促进毛细血管生成,FGF-2倾向于促进小动脉生成[53]。国外许多研究表明,在同样条件下,VEGF和FGF2联合刺激毛细血管内皮细胞的作用比二者单独刺激明显增强,表明二者具有协同作用[11] [54] [55]。Pepper等学者在小牛上发现,随着FGF2水平升高,VEGF的表达也增加[54]。Seghezzi等学者通过小鼠试验发现FGF-2主要通过自分泌和旁分泌促进VEGF在EC和壁细胞中的产生,并进一步发现FGF2既可以通过细胞内途径上调VEGF的表达,也可以直接促进小鼠视网膜血管生成[11]。Saadeh 等也在胎鼠上发现随FGF-2的增加,VEGF表达增加[55]。国内褚晓凡等学者在SD大鼠上通过测定局部脑缺血灶的VEGF、FGF2在不同时间和部位的水平和分析其相互关系发现,缺血会诱导血管EC分泌FGF2增加直接促进血管内皮的增殖和迁移,同时刺激受损的血管壁细胞上调VEGF的表达,进而促进与VEGF协同作用的血管EC的增殖,并且VEGF、FGF2表达水平达到高峰几乎是同时的[56]。由此表明,FGF2可以通过促进VEGF的表达从而直接或间接发挥其促进新生血管生成及血管通透性增加的作用。同时Seghezzi等、Tsunoda等学者研究发现VEGF也可作为FGF2发挥其生物学功能的重要中间介质,并且也能上调FGF2的表达[11] [57]。VEGF和FGF-2都属于血小板相关衍生生长因子,他们可以协同地通过靶向作用于血管EC而促进血管内皮增殖、迁移、通透性增加以及新生血管形成。糖尿病由于葡萄糖过量堆积导致PRC和PRE受损从而引起缺氧,长期缺氧引起HIF-1通过隐性膜蛋白1 (Latent Membrane Protein 1, LMP-1)诱导而大量积聚,HIF-1对其下游基因VEGF、FGF2都具有较强的调控作用,最终引起VEGF、FGF2的表达上升[58]。目前已知FGF-2通过激活P44/P22-MAPK信号通路来提高VEGF的释放[59]。后来Tokuda等学者在之前的结果上进一步发现FGF2、VEGF发生协同作用更重要的是通过应激活化蛋白激酶(Stress-Activated Protein Kinase, SAPK)的磷酸化来实现的[60]。另外,在肿瘤研究领域,有学者发现抗VEGF靶点治疗产生耐药性的主要原因是FGF2的升高[61],表明VEGF与FGF2双靶点治疗在许多疾病上是重点研究方向。

VEGF在糖尿病及DR、DME的密切联系已被我们熟知,而FGF2与糖尿病及DR、DME的相关性研究相对较少。目前有国外学者Aleksandra Tokarz等研究者发现,与健康对照组相比,糖尿病患者细胞外囊泡的VEGF和FGF2的浓度显著升高[62],另外Hill等国外学者在足月妊娠受试者发现,与正常孕妇相比,妊娠合并妊娠期糖尿病的孕妇的FGF2的水平增高[63]。表明FGF2同VEGF一样与糖尿病存在密切联系,这可能与糖尿病患者的长期高糖状态造成的缺氧引起HIF-1及AGEs等的产生从而促进VEGF和FGF2的分泌相关,但具体关联的机制需进一步探究。由于FGF2的促血管生成及增加血管通透性的功能及其促进VEGF表达上调的作用与DR及DME的发病在机理上是密切相关的,所以目前有学者开始探究二者之间可能的相关性。国内外学者通过在2型糖尿病Goto Kakizaki (GK)大鼠模型及肥胖的2型糖尿病Zucker diabetic fatty (ZDF)大鼠模型中发现随着RNV的生成增加,VEGF和FGF2表达水平均上升[64] [65],表明VEGF、FGF2的升高与GK大鼠模型和ZDF大鼠模型RNV的生成呈正相关。国内外学者通过横断面研究发现FGF2水平在NDR、NPDR、PDR组别之间依次上升,表明了FGF2与DR的发生相关,并且与DR的严重程度有关[66] [67]。另外国外Jonas等学者通过研究发现在DME、年龄相关性黄斑变性(Age-related Macular Degeneration, AMD)和健康对照组之间,VEGF和FGF2在DME眼中的浓度明显高于AMD或正常对照组,此证据更有力说明了FGF2可能在因糖尿病所致的黄斑水肿中起着重要作用[68]

5. 结论

糖尿病视网膜病变所致的DME是视力丧失的主要原因,尽管抗VEGF治疗取得了显著进展,但其临床局限性促使研究者探索新的治疗靶点。FGF2作为重要的促血管生成因子,通过与VEGF协同作用参与DME的病理进程,并可能是抗VEGF治疗耐药的关键机制。基础和临床研究已证实FGF2与DR严重程度的相关性,其作为生物标志物和治疗靶点的潜力值得深入探索。

综上所述,把FGF2作为DME的一个干预靶点具有潜在的临床应用价值,国内目前关于DME与FGF2的相关性探究较少,本文将FGF2与DR、DME的关系进行详细的梳理,有利于未来针对DR、DME与FGF2的相关性进行研究,为治疗DME提供新思路,最终改善DME患者的视觉预后。

NOTES

*通讯作者。

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