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小梁网泵衰竭在青光眼发病中的作用机制的研究进展

Research progress on the mechanism of trabecular meshwork pump failure in the pathogenesis of glaucoma

来源期刊： 眼科学报 | 2024年7月 第39卷 第7期： 325-331 发布时间：2024-07-28 收稿时间：2024/9/19 10:12:41 阅读量：601
作者：
车煜彤,
蒋宇凡,
吴彩清,
杨扬帆,
关键词：
青光眼小梁网房水流出泵
glaucoma trabecular meshwork aqueous outflow pump
DOI：
10.12419/24073004
收稿时间：
2024-06-02 
修订日期：
2024-06-23 
接收日期：
2024-07-12 
青光眼是一组以视盘萎缩凹陷、视野缺损以及视力下降为共同特征的视神经退行性疾病，也是世界首位不可逆性致盲眼病，导致患者生活质量降低、引起极大卫生经济负担。但其发病机制尚不明确，促进房水排出从而降低眼内压仍是目前减缓疾病进展的唯一治疗手段。房水排出的主要途径是经由小梁网进入Schlemm's管最后汇入巩膜外静脉，因此小梁网在调节房水排出以及平衡眼内压方面发挥重要作用。近年来，体内以及体外房水排出测量技术和小梁网成像技术不断突破，众多研究表明小梁网存在压力依赖的节律性搏动，在房水的脉冲式排出中起到关键作用，但在青光眼中这种搏动随疾病的进展减弱甚至消失。文章以小梁网的泵理论为核心，总结青光眼中房水排出的最新研究进展，并从恢复小梁网功能的角度出发探索可能有效的治疗策略，为青光眼的临床诊治提供新的思路。
Glaucoma, a group of optic nerve degenerative diseases, is characterized by papillary atrophy, visual field defects, and decreased vision. It is also the leading cause of irreversible blindness worldwide, significantly reducing patients’ the quality of life of patients and posing considerable health economic burdens. However, the pathogenesis of glaucoma remains unclear, and promoting aqueous humor outflow to reduce intraocular pressure is the only treatment option available to slow disease progression. The main pathway for aqueous humor outflow is through the trabecular meshwork into Schlemm's canal and finally into the episcleral veins, highlighting the crucial role of the trabecular meshwork in regulating aqueous humor outflow and maintaining intraocular pressure balance. In recent years, there have been notable breakthroughs in in vivo and in vitro aqueous humor outflow measurement techniques and trabecular meshwork imaging technologies.Many studies suggest that the trabecular meshwork exhibits pressure-dependent rhythmic pulsation, playing a crucial role in the pulse-like outflow of aqueous humor. Unfortunately, in glaucoma, this pulsation weakens or even disappears as the disease progresses. This article focuses on the trabecular meshwork's pump theory and summarizes the latest research progress in aqueous humor outflow in glaucoma, exploring potential effective therapeutic strategies aimed at restoring trabecular meshwork function. This provides new insights for the clinical diagnosis and treatment of glaucoma.

文章亮点

1.关键发现

• 众多研究结果表明房水不是被动地、持续地排出，而是在由小梁网与 Schlemm' s 管等组成的机械泵的介导下呈节段性、脉冲性排出。然而研究者在青光眼患者中观察到，房水的脉冲式排出和小梁网节律性搏动减弱甚至消失，且常与疾病进展呈正相关，这提示小梁网泵衰竭在青光眼的发病机制中具有重要意义。

2. 已知与发现

• 青光眼的发病机制尚不明确，促进房水排出从而降低眼内压仍是目前减缓疾病进展的唯一手段。房水排出的主要途径是经由小梁网进入 Schlemm' s 管最后汇入巩膜外静脉，因此小梁网在调节房水排出以及平衡眼内压方面发挥重要作用。然而目前对于青光眼中房水排出以及小梁网泵的作用机制认识仍然较少。

3. 意义与改变

• 本文以小梁网的泵理论为核心，总结青光眼中房水排出的最新研究进展，并从恢复小梁网功能的角度出发探索可能有效的治疗策略，为青光眼的临床诊治提供新的思路。

       青光眼是一组以视盘萎缩凹陷、视野缺损以及视力下降为共同特征的视神经退行性疾病，也是世界首位不可逆性致盲眼病。伴随视网膜神经节细胞的进行性凋亡与轴突丢失，患者视力逐步丧失，并导致其生活质量降低，引起极大卫生经济负担。然而青光眼的发病机制尚不明确，促进房水排出从而降低眼内压力仍是目前减缓疾病进展的唯一有效治疗手段。房水排出途径包括经典的小梁网途径以及葡萄膜巩膜途径等非经典途径，其中75%~85%房水经由小梁网进入Schlemm' s管最后汇入巩膜外静脉，因此小梁网在调节房水排出以及平衡眼内压力方面发挥重要作用。近年来，体内以及体外房水排出测量技术和小梁网成像技术不断突破，众多研究表明小梁网存在压力依赖的节律性搏动，在房水的脉冲式排出中起到关键作用。然而研究者在青光眼患者中观察到，房水的脉冲式排出和小梁网节律性搏动减弱甚至消失，且常与疾病进展呈正相关，这提示小梁网泵衰竭在青光眼的发病机制中发挥重要作用。本文以小梁网的泵理论为核心，总结青光眼中房水排出的最新研究进展，并从恢复小梁网功能的角度出发探索可能有效的治疗策略，为青光眼的临床诊治提供新的思路。

1 小梁网的结构与功能

       小梁网位于Schwalbe线与巩膜突之间的巩膜内沟，并延伸至睫状体及虹膜基质，其外侧后2/3与Schlemm' s管相邻，具有引流房水的功能[1]。组织学上小梁网由3个结构不同的区域组成，分别为葡萄膜小梁网、角巩膜小梁网和近小管小梁网(juxtacanalicular tissue, JCT)。葡萄膜小梁网与角巩膜小梁网是由小梁结构交错形成的海绵状组织，每束小梁均由胶原纤维核心以及其外围的弹力纤维和最外层被覆的小梁网细胞组成，切除这2个区域的小梁网对于房水排出阻力不会产生明显影响[2]。JCT则无小梁结构，是由附着于基底膜上的2~5层小梁网细胞通过长的细胞突起相互连接构成，这些小梁网细胞被纤连蛋白、透明质酸、糖胺聚糖等多种致密的细胞外基质(extracellular matrix, ECM)包裹[3]。既往研究显示，原发性开角型青光眼患者的JCT表现出细胞骨架结构异常、ECM沉积等，提示该区域是产生房水排出阻力的主要部位[4]。
       小梁网细胞具有多种生理功能以及细胞特性。葡萄膜与角巩膜区域的小梁网细胞主要表现内皮细胞和吞噬细胞特性，不仅可以产生硫酸肝素、组织纤溶酶原激活物等抗血栓形成物质[5]，从而防止ECM过度沉积，而且可以吞噬房水中的细胞碎片、色素颗粒等杂质，进而避免房角栓塞[6]。近年的研究显示，JCT的小梁网细胞具有平滑肌细胞的舒缩特性，可以通过改变自身空间结构和滤过面积等调节房水排出阻力[7]。例如可以通过膜片钳测量细胞电位、长度传感器测量组织长度、眼前节灌注测量房水流出等技术，记录卡巴胆碱、内皮素等引起的小梁网收缩活动[8-9]。在分子水平上也已证实小梁网中存在三磷酸腺苷依赖性钾通道(ATP-dependent potassium channel)、L型钙通道等与细胞收缩密切相关且在平滑肌中广泛表达的离子通道[10]。此外，小梁网细胞内平滑肌肌球蛋白、α-平滑肌肌动蛋白(alpha-smooth muscle actin, α-SMA)以及交联肌动蛋白网络等的发现，也为小梁网具有平滑肌的舒缩特性提供有力证据[11]。

2 房水的脉冲式排出与小梁网节律性搏动

       早期研究者已在离体灵长类动物眼和人眼中使用扫描电子显微镜、透射电子显微镜等技术[12-13]，对于起到锚定作用的小梁网板层结构、保证房水单向流动的Schlemm' s管瓣膜结构等房水排出系统的解剖基础进行描述。带状扫描共聚焦显微镜成像技术除被应用于脑组织以外，也被应用于对房水排出系统进行三维重建，并且具有快速高效、伪影较少等优点[14]。双光子自体荧光显微镜成像技术由于不使用固定液因而组织结构变形程度较低，并且由于手术可以暴露小梁网及Schlemm' s管等而且深部组织成像方面更具优势[15]。光学相干断层扫描技术(optical coherence tomography, OCT)在离体组织的房水排出系统成像方面的应用则更加广泛，例如光谱域光学相干断层扫描技术(spectral domain optical coherence tomography, SD-OCT)、扫频源光学相干断层扫描技术(swept source optical coherencetomography, SS-OCT)、光学相干断层扫描血管造影技术(optical coherence tomography angiography, OCTA)等[16-18]，然而，图像分辨率较低、难以辨别血管中的液体是房水还是血液等，均为这些技术共同面临的难题。
       近年来，体内房水排出测量技术和小梁网成像技术不断突破，使得在活体内观察房水排出系统成为可能。既往曾有研究者在术中对人眼使用黏弹剂扩张Schlemm's管并且造口，通过前房角镜观察眼球减压所引起的血液回流[19]。也有学者经由微导管直接将吲哚菁绿(indocyanine green, ICG)注入至Schlemm' s管，然后通过手术显微镜来观察荧光素向前房及巩膜外静脉的渗漏情况[20]。虽然这些方法提供了较清晰的体内房水排出系统图像，但却不能显示生理状态下的房水排出情况。随后有研究者总结前述多种成像技术的优点，在对离体猪、牛以及人眼检测成功的基础上[21-22]，对活体非人灵长类动物开展房水血管造影(Aqueous Angiography)，通过前房持续输注IGG并用特殊成像系统进行观察，在尽可能接近生理状态的情况下，发现房水排出呈现节段性、脉冲性[23]。尽管这项技术仍是侵入性的，但这对进一步明确房水排出的动力学具有重要意义。
       血红蛋白视频成像(haemoglobin video Imaging, HVI)技术则可以无创地用裂隙灯显示房水排出过程，含红细胞的血液在明亮的背景下较暗而房水则呈现出透亮的水柱[24]，由此可以观察到房水与血液交界面的来回移动，为房水的脉冲式排出提供又一直观证据。此外HVI技术也揭示了部分房水静脉的特征[25]，例如局部压迫房水静脉可以引起房水重新流向附近的巩膜静脉中，以及房水与血液交界面的来回移动与心律相关。早期便有学者提出房水排出系统可能存在与心动周期同步的节律性搏动[26]。近年来，在多普勒OCT基础上发展的相敏光学相干断层扫描(phase-sensitive optical coherence tomography, PhS-OCT)技术可以直观地记录到房水脉冲式排出中小梁网与心动周期同步的节律性搏动[27]，并且可以通过记录小梁网的位移变化，评估Schlemm' s管植入缝线、使用毛果芸香碱滴眼液等干预因素对其节律性搏动的影响[28]，这为房水排出系统的结构及动力学研究提供了更加直观的证据。
       众多对于房水排出的动力学以及体内房水排出系统成像的研究表明，房水不是被动地、持续地排出，而是在由小梁网与Schlemm' s管等组成的机械泵的介导下呈节段性、脉冲性排出。在生理情况下，心脏收缩导致眼灌注压升高，脉络膜扩张、眼内压(intraocularpressure, IOP)升高，小梁网收缩、移向Schlemm' s管引起管腔变窄、静水压力增加，房水自Schlemm' s管进入巩膜外静脉增加；心脏舒张导致眼灌注压降低，脉络膜缩小、IOP降低，小梁网舒张、远离Schlemm' s管，引起小梁孔隙增加，房水自前房进入Schlemm' s管增加。当然，眼球运动、局部压迫及情绪波动等引起的IOP升高也会对机械泵产生影响，进而动态调节房水排出，实现IOP的平衡。

3 小梁网泵衰竭在青光眼发病中的作用机制

       在正常眼与高眼压眼的对比中可发现，小梁网泵构建的Schlemm' s管与前房(Anterior chamber, AC)间的压力梯度常被逆转，血液无法回流至Schlemm' s管，房水的脉冲式排出现象减弱甚至消失，且常与疾病进展呈正相关[29-30]。饮水试验可使每搏输出量快速增加，正常眼可促进房水排出进而导致IOP降低，而青光眼则表现为IOP升高，故临床上可用于检测青光眼中的小梁网泵衰竭[31]。研究者在对离体人眼前节增加灌注压力时发现，房水排出阻力增加并且小梁网中胶原蛋白、整联蛋白等的表达增加[32]；给予体外培养的小梁网细胞机械牵拉，模拟体内眼压波动引起的生理性机械拉伸，可以诱导小梁网细胞交联肌动蛋白网络(cross-linked actin network, CLAN)形成增加，从而抑制小梁网的收缩[33]。这提示小梁网组织ECM过度沉积以及小梁网细胞收缩功能障碍，是青光眼发生、发展过程中小梁网泵衰竭的重要原因。
       小梁网组织ECM过度沉积与多种因子表达失调有关。已有研究表明原发性开角型青光眼患者的房水中转化生长因子-β2(transforming growth factor-β2, TGF-β2)含量增加，并且使用TGFβ2处理离体灌注的眼前节器官可导致其流出功能降低，这与经典的TGFβ-Smad信号通路被激活进而导致细胞外胶原蛋白以及纤连蛋白等的沉积增加有关[34]。此外基质金属蛋白酶(matrix metalloproteinases, MMPs)及其抑制物失衡也参与到小梁网的ECM重塑，给予体外培养的小梁网细胞机械牵拉或者增加离体眼前节器官培养的灌注压力，可表现为MMPs活性升高、其内源性抑制物的表达降低[35]。ECM重塑也会影响小梁网细胞的生物学行为，例如基质变硬增加小梁网细胞对于表皮生长因子(epidermal growth factor, EGF)的敏感性，也可激活肌动蛋白结合蛋白RhoA，并且影响β-连环蛋白以及YAP/TAZ等的信号传导[36]。
       小梁网细胞收缩功能障碍则与细胞骨架结构异常密切相关。小梁网细胞中的肌动蛋白微丝具有多种结构，通常多呈线性排列形成肌动蛋白束即应力纤维，介导细胞收缩、吞噬等生理活动。但在青光眼患者的原代小梁网细胞中发现，肌动蛋白微丝重新排列，使得不常见的圆顶状CLAN形成增加[37]。也有研究表明，地塞米松(dexamethasone, DEX)、TGF-β等的处理增加小梁网细胞CLAN形成，同时小梁网的细胞增殖、吞噬以及收缩功能受到抑制，并且上述变化在去除药物后可以逆转[38]。此外在青光眼动物模型中的研究结果也证明，整联蛋白αvβ3可以感受IOP升高所带来的机械应力进而表达上调，并且通过αvβ3整联蛋白/Trio/Rac 1信号传导途径与β1整联蛋白/PI3K信号传导途径会聚调节肌动蛋白形态变化，最终影响小梁网细胞的收缩功能[39]。

4 促进小梁网功能修复的药物以及手术治疗

       临床上，部分传统的滴眼液可以增加小梁网的节律性搏动和房水的脉冲式排出，例如缩瞳剂、肾上腺素以及前列腺素。缩瞳剂如毛果芸香碱可以使睫状肌收缩并增加巩膜突的张力，进而牵拉小梁网，使其在孔隙增大的同时可远离Schlemm' s管外壁，引起小梁网的节律性搏动增强，继而增加房水的脉冲式排出[40]。肾上腺素能药物如溴莫尼定起效快但维持时间较短，主要作用于毛细血管前小动脉，通过减少其血流量降低巩膜外静脉的压力，即降低房水排出的后负荷而使房水排出增加[41]。前列腺素类药物如拉坦前列素可以引起脉络膜血管的舒张，增加其振荡幅度进而引起小梁网压力依赖性的节律性搏动的增强，从而起到促进房水排出的作用[42]。近年来新兴的Rho激酶抑制剂(Rho kinase inhibitors, ROCKi)可以直接作用于小梁网，通过调节细胞骨架形态从而抑制组织收缩，同时增强小梁网细胞形成孔隙的能力，降低房水排出阻力[43]。
       手术治疗也可部分解决小梁网组织的功能障碍。年龄增长可使小梁网的弹性纤维更多向胶原纤维转变，导致组织弹性降低、节律性搏动减弱。氩激光小梁成形术(argon laser trabeculoplasty, ALT)可以通过热效应诱导组织胶原收缩[44]，增强小梁网对眼内压力波动的响应，从而促进房水流出。选择性激光小梁成形术(laser trabeculoplasty, LASIK)也通过热效应使小梁网收缩，但由于仅使用特定波长激光，所需能量较低，因而手术所产生的瘢痕组织较少[45]，在临床的应用更加广泛。一项长期随访的临床试验结果表明，LASIK可以安全有效地治疗开角型青光眼，与滴眼液治疗相比可以提供更好的长期控制效果，减少6年内的手术需求[46]。微脉冲经巩膜激光治疗(micropulse transscleral laser therapy, MP-TLT )可引起睫状肌的收缩与小梁网结构改变，优点在于激光无法穿透深部组织，因此不会损伤睫状上皮[47]，这是与传统技术相区别的重要特点。

5 总结与展望

       近年来，体外及体内的房水排出测量技术和小梁网成像技术不断突破，众多研究结果表明房水不是被动地、持续地排出，而是在由小梁网与Schlemm' s管等组成的机械泵的介导下呈节段性、脉冲性排出。青光眼中小梁网的节律性搏动与房水的脉冲式排出现象减弱甚至消失，小梁网泵衰竭引起房水蓄积进而导致IOP升高，这与小梁网组织ECM过度沉积以及小梁网细胞收缩功能障碍密切相关。发展更加安全有效、图像清晰、便于在临床推广应用的成像技术，继续完善小梁网的机械泵理论，探究参与这一过程的具体分子机制，明确小梁网节律性搏动在房水的脉冲式排出中的意义，从而为青光眼的早期诊断以及临床治疗提供新的思路，是目前亟待解决的问题。

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47、Moussa K, Feinstein M, Pekmezci M, et al. Histologic changes following continuous wave and micropulse transscleral cyclophotocoagulation: a randomized comparative study[ J]. Transl Vis Sci Technol, 2020, 9(5): 22. DOI: 10.1167/tvst.9.5.22.Moussa K, Feinstein M, Pekmezci M, et al. Histologic changes following continuous wave and micropulse transscleral cyclophotocoagulation: a randomized comparative study[ J]. Transl Vis Sci Technol, 2020, 9(5): 22. DOI: 10.1167/tvst.9.5.22.
1、中山大学高校基本科研业务费重点项目(23xkjc022)。
This work was supported by Fundamental Research Funds for the Central Universities, Sun Yat-sen University(23xkjc022).()
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发布于: 2022-12-01
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