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航天飞行相关的神经 - 眼综合征及地面模拟实验及对策研究进展

Research progress on spaceflight associated neuroocular syndrome, ground simulation experiments and countermeasures

来源期刊: 眼科学报 | 2024年2月 第39卷 第2期 107-112 发布时间:2024-02-28 收稿时间:2024/6/6 17:03:11 阅读量:858
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关键词:
航天飞行相关的神经-眼综合征发病机制地面模拟实验缓解对策
spaceflight associated neuro-ocular syndrome ground simulation experiment pathogenesis mitigation measures
DOI:
10.12419/24041201
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航天飞行相关的神经-眼综合征(spaceflight associated neuro-ocular syndrome,SANS)是指宇航员在长时间航天飞行期间和之后观察到的包括视盘水肿、后极部眼球扁平、脉络膜视网膜皱褶和远视飘移等在内的一系列眼部、神经和神经影像学表现,可能会对飞行员造成短期或长期的视力改变、认知影响或其他有害的健康影响,因此,明确SANS的发病机制,进行有效的地面模拟实验及制定对应的缓解对策对未来更远、更久的航天飞行具有重要的意义。目前SANS的发病机制主要有颅内压升高、脑血容量波动与血管重塑、脑和视交叉向上移位、眼淋巴系统流动失衡、细胞毒性水肿、眼眶脂肪肿胀等。国际上研究较多的地面模拟实验为6°头朝下倾斜卧床休息,能够重现SANS的各种表现,包括视神经鞘扩张、视网膜神经层增厚、脉络膜厚度增加和视盘水肿;此外,干浸浴、抛物线飞行等地面模拟实验也观察到了SANS的部分表现。下体负压作为缓解对策能减轻脉络膜增厚和视神经鞘直径增加,正压力护目镜也有望成为应对SANS的有效对策。该文就国内外相关进展进行综述。
Spaceflight associated neuro-ocular syndrome (SANS) refers to a series of ocular, neurological and neuroimaging manifestations observed in astronauts during and after long-term space flight, including optic disc edema, posterior globe flattening, choroid-retinal folds, and hyperopic refractive shift. These effects may have short-term or longterm on vision , cognitionand other aspects of astronauts’ health. Therefore, elucidating the pathogenesis of SANS, conducting effective ground simulation experiments, and developing corresponding mitigation strategies are crucial for enabling deeper and longer-duration space exploration. Current understanding of the pathogenesis of SANSincludes increased intracranial pressure, fluctions in cerebral blood volume and vascular remodeling, upward displacement of the brain and optic chiasm, imbalance in ocular lymphatic system flow, cytotoxic edema, and orbital fat swelling, etc. Among the various ground simulation experimens, the 6 ° head-down tilt bed rest has been extensively studied and has been shown to replicate various manifestations of SANS, such as optic nerve sheath expansion, retinal nerve layer thickening, choroidal thickness increase and optic disc edema. Additionally, dry immersion and parabolic flight have also demonstrated some aspects of SANS during ground simulation experiments.The use of lower body negative pressure has been identified as a potential countermeasure to reduce choroidal thickening and increase in optic nerve sheath diameter. Furthermore, positive pressure goggles are also expected to be an effective strategy for mitigating the effectsof SANS.This article provides a comprehensive review of the relevant advancements in the field of SANS, both domestically and internationally.

文章亮点

1. 关键发现

  SANS的发病机制有颅内压升高、脑血容量波动与血管重塑、脑和视交叉向上移位、眼淋巴系统流动失衡、细胞毒性水肿、眼眶脂肪肿胀等。

2. 已知与发现

   国际上研究较多的地面模拟实验为 6°头朝下倾斜卧床休息。
   下体负压作为缓解对策能减轻脉络膜增厚和视神经鞘直径增加。

3. 意义与改变

   明确SANS的发病机制,进行有效的地面模拟实验及制定对应的缓解对策对未来更远、更久的航天飞行具有重要的意义。

   航天飞行相关的神经-眼综合征(spaceflight associated neuro-ocular syndrome,SANS)最初也被称为视觉障碍和颅内压综合征(visual impairment and intracranial pressure syndrome,VIIP)[1],是指宇航员在长时间航天飞行期间和之后观察到的一系列的眼部、神经和神经影像学表现,这些眼部表现包括视盘水肿、后极部眼球扁平、脉络膜视网膜皱褶和远视飘移等[2]
鉴于在航天飞行过程中会发生眼部和大脑结构的变化,这些变化可能导致短期或长期的视力改变、认知影响或其他有害的健康影响,美国航天局对SANS的“可能性和后果”评级相对较高,表明长时间航天飞行对宇航员健康和工作表现有潜在风险[3]。因此,进一步了解SANS和制定对应的措施是未来太空探索任务的高度优先事项。本文将回顾关于这一独特现象的各种潜在发病机制的假设,并探讨正在用于进一步了解SANS的地面模拟实验,以及正在开发的用于减轻SANS的潜在对策,这些领域的研究结论对于未来降低未来太空飞行任务的风险至关重要。

1 SANS的发病机制

1.1 颅内压升高

自2011年Mader等[4]首次报道SANS的表现以来,出现了关于SANS发病机制的多种假说。SANS最初被称为VIIP,被认为是由于微重力时出现的头颅液体移位导致颅内压(intracranial pressure,ICP)升高,压力可能会转移到眼眶视神经鞘,导致视神经鞘扩张、轴浆流动停滞和眼球变平[5],进而引起视盘水肿和短暂视觉模糊,类似于地面特发性颅内压升高(idiopathic iIntracranial hypertension,IIH)。然而,SANS不伴有IIH的其他典型体征,如慢性头痛、脉搏同步性耳鸣、斜视,并且IIH大多数表现为双侧对称的视盘水肿,而SANS的视盘水肿多为单侧不对称[5],另外目前宇航员长期太空飞行后测量的ICP值略高于正常至临界值,没有地面IIH看到的ICP明显升高。这些初步表明,SANS可能不仅是由于ICP升高引起的。因此,将视觉障碍和VIIP更名为航天飞行相关的SANS更为合适,以涵盖SANS发病机制的更广泛范围[6]

1.2 脑血容量波动与血管重塑

Strangman等[7]提出SANS不是由静态ICP升高引起的,而是由脑动脉搏动相关的慢性冲击过程中产生的颅内压升高引起,类似于水力学当中的“水锤效应”(水流冲击对管道设备造成的危害),更重要的是,许多研究表明,动脉搏动的变化可诱导血管重塑,以帮助代偿搏动的增加,值得一提的是,Lim等[8]的研究表明血容量搏动增加与血液中总同型半胱氨酸升高有关。更普遍的观点是,同型半胱氨酸与血管功能障碍或重构有关[9],并且同型半胱氨酸水平升高与SANS导致的视力变化有关[10]。Strangman等[9]运用近红外漫反射光谱法,研究在高碳酸血症环境下头朝下倾斜卧床休息时的脑血容量搏动,发现在动脉扩张时,固定采样区域内的脑血容量增加,并且通过阶段性地增加固定大小的颅弓内的血容量,从而产生典型的ICP波形,也观察到一种水锤效应,导致血管重塑,血管重塑同样解释了SANS在宇航员返回地球时还持续存在。

1.3 脑和视交叉向上移位

Roberts等[11]进行了一项研究,通过比较宇航员在短期和长期太空飞行后大脑的核磁共振成像发现,所有进行长时间航天飞行的宇航员的大脑都有向上移动的现象,而短期太空飞行组的宇航员则没有这些表现。Shinojima等[12]基于这个现象,提出了一项假说,假设在航天飞行中,大脑向上移动引起视交叉向上移动,将视神经向后牵拉,由于眼眶处骨膜与视神经鞘的硬脑膜相连,视神经的向后移位可能导致视神经鞘的扩张和弯曲,即视神经鞘直径增加,这解释了一些SANS中发现的视神经鞘直径增加。此外,由于硬脑膜对眼球的恢复力,视神经受到的向后力会导致眼球变形,即眼球变平。

1.4 眼淋巴系统流动失衡

Mathieu等[13]提供了脑脊液通过血管旁间隙进入小鼠眼眶视神经的第一个证据,并认为这种途径可能与包括青光眼在内的视神经疾病高度相关,Wang等[14]通过玻璃体内注射荧光结合的人淀粉样蛋白-β,以及随后对注射眼睛的视网膜和视神经进行共聚焦和立体荧光成像检查,证明了眼淋巴通路的存在,Jacobsen等[15]通过检查鞘内注射的脑脊液示踪剂是否分布在视神经眼眶和颅内段以及中央视觉通路的血管外空间,进一步证明了蛛网膜下腔和血管外腔人类视觉通路之间的脑脊液存在直接交流,尹相云等[16]运用空间转录组学、组织透明化技术、共聚焦成像、染料追踪等方法发现视神经鞘具有淋巴管,并且眼后节有一个独特的淋巴引流系统,解剖学上与颅外颈淋巴结深处的中枢神经系统脑膜淋巴网络相结合,Wostyn等[17]提出了一个假设框架,根据该框架,宇航员的ODE可能至少部分是由于较高压力的视神经周围脑脊液沿着视网膜中央动脉周围的血管周围间隙进入视神经和视盘造成的。

1.5 细胞毒性水肿

Galdamez等[18]以脑水肿的病理生理学为模型,假设SANS中存在炎症或氧化应激途径机制,认为静脉淤滞可能通过静脉和毛细血管扩张和渗漏导致视盘水肿,静脉淤滞也会导致代谢活性和细胞营养物质传递的中断,腺苷三磷酸(adenosine 5'triphosphate,ATP)生成就会受损,而ATP耗竭会导致Na+/K+ATP酶活性降低,细胞内低Na+环境就无法维持,从而引起轴突水肿。

1.6 眼眶脂肪肿胀

Matthew等[19]通过有限元建模计算模拟眼眶压力增加对眼结构的影响,并将预测结果与长期暴露在微重力下的眼部体征进行比较,发现随着眼眶脂肪含水量的增加,即眼眶脂肪肿胀程度的增加,该模型预测了眼球的少量前向运动、与眼球扁平化相关的轴向长度缩短以及与诱发脉络膜褶皱相关的脉络膜受压或张力改变,轴向长度、眼球扁平化和脉络膜褶皱的变化,与已经报道的宇航员的眼部发现一致,这种关于眼眶脂肪肿胀引起的SANS的生物力学理论可以用单一的机制来解释所有报道的SANS表现。

2 SANS的地面模拟实验

与在国际空间站上进行的SANS研究相比,地面的航天模拟研究通常具有更大的样本量,每例受试者能收集更多的数据,实验具有更广泛的测试能力,并且大大降低了成本。常用的微重力地面模拟实验有落塔法、抛物飞行法、悬吊法、水浮法、气悬浮法[20]和干浸浴、头朝下倾斜休息、仰卧位休息,虽然目前还没有可完全模拟太空失重环境的地面模拟实验,但头朝下倾斜卧床休息(head-down tilt bed rest,HDTBR)可以持续卸载垂直方向的重力[21],通过改变身体上的引力矢量,增加液体向头部转移,产生类似于微重力中的头颅液体位移[22-23],能够重现SANS的各种表现,包括视神经鞘扩张、视网膜神经层增厚、脉络膜厚度增加和视盘水肿[24-28],Sater等[29]进行了基于核磁共振成像的60 d严格头朝下倾斜卧床休息后眼球变平的定量研究,测量到了由于眼球变平引起的眼球后极部位移。HDTBR是将受试者放置在倾斜6°(6 °是模拟航天飞行失重的国际标准[30])的床上,将头部靠近地面并抬高脚进行实验。值得一提的是,对于严格的HDTBR,受试者不能改变这种姿势或使用枕头支撑头部,Lawley等[31]研究表明,仰卧位时将头部放在枕头上会持续降低ICP,这将抵消可能出现的SANS。此外,Arbeille等[32]通过三维超声测量干浸浴前后的颈静脉、门静脉和甲状腺体积,以及使用经颅多普勒超声测定大脑中静脉流速,发现干浸浴2 h会导致大量液体向身体上部转移,但利用耳蜗对音频刺激的反应推导的颅内压未见明显差异,Kermorgant等[33]研究表明,干浸浴3 d会导致视神经鞘直径的快速和持续增加。Lawley等进行了抛物线飞行研究,进行了真正的0重力及其相关的液体位移模拟,通过Ommaya储液囊直接测量颅内压,发现在短暂的微重力期间,ICP与地面仰卧姿势相比有所降低,但没有降低到直立地球90 °的水平[30]。虽然地球上没有SANS的精确模拟实验,但随着未来航天飞行越来越多,持续时间越来越长,选择适当的地面模拟实验变得越来越重要。

3 SANS的缓解对策

3.1 下体负压下体负压(lower body negative pressure,LBNP)是通过使人体下半身暴露于负压环境中,从而与上半身形成压力梯度,引起体液从上半身向下半身转移的一种方法[34], 可在一定程度上抵消失重或微重力状态下的血液重新分布带来的影响,有助于抵消微重力环境中头颅液体的转移,理论上认为这有助于缓解SANS。LBNP作为SANS的对策已受到重点关注[35-38]。下体负压已被用于航天期间的心血管生理学研究,从而确立了其作为SANS的一种有希望的对策[39]。Petersenet等[34]对安装了Ommaya储液囊的个体进行了一项地面模拟颅内压升高的下体负压研究,观察到下体负压后颅内压的下降。Hearon等[39]进行了地面严格仰卧位下的每晚8 h下体负压研究,观察到下体负压减轻了脉络膜面积和体积的增加程度,睡眠中的下体负压可能是应对长期航天任务引起SANS的有效对策。
标准的下体负压舱极其笨重,因此被排除在国际空间站或地球轨道以外的任何航天飞行任务之外。由于负压舱的体积很大,在产生更强的压力时需要更多的功耗,此外,负压舱是完全静态的,需要用户长时间留在里面。目前,俄罗斯航天局在国际空间站有自己的下体负压装置,称为Chibis太空服,这种对抗装置没有机动性,要求始终连接到固定的真空泵装置和壁挂式电源[40],Ashari等[41]基于James等的研究设计并开发了一种小型、无栓系、灵活的舱内活动服,为宇航员在未来的任务中提供了高效和有效的对策。此外,Marc等[42]研究发现,静脉收缩大腿袖带可减轻干浸浴引起的视神经鞘直径增加。

3.2 正压力护目镜

眼科系统高度受眼内压(intraocular pressure,IOP)和ICP的调节,跨层流压力梯度(translaminar pressure gradient,TLPG)是指通常较高的眼压和较低的颅内压之间的关系,航天飞行引起的ICP增加超过眼压增加,导致负的和向前的跨层流压力梯度,这与视盘、筛板和视神经蛛网膜下腔的不良变化有关[1]。Scott等[43]提出,通过泳镜适当增加眼压来调节TLPG,其使用了一个15°头朝下倾斜的研究平台,观察到TLPG随着护目镜的使用而增加,并认为需要继续研究人工升高眼压,以进一步了解护目镜是否可以作为SANS的对策。

4 展望

随着我国载人航天飞行向着常态化、长期化发展,考虑到在长时间航天飞行过程中可能出现视力丧失和由此导致的航天任务受损,进一步研究和减轻SANS显得尤为重要,目前关于SANS研究的报道大多来自于国外研究,尽管国外对十多年前首次描述的眼部发现取得了重大进展,但对个体风险因素、潜在机制和长期健康后果的认识仍存在许多有待解决的问题,因此,加强航天飞行中SANS相关表现的监测能力,尤其是ICP,进一步优化SANS的地面模拟实验和对策,对宇航员的健康和航天飞行任务至关重要,特别是未来更远、更久的航天行任务将使宇航员暴露在比目前观察到的更长的微重力环境中,研究SANS的病理生理学,明确SANS的发病机制,进行有效的地面模拟实验及制定对应的缓解对策,将为未来进行更远、更久的航天飞行提供更强有力的保障。

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1、 四川省自然科学基金(2023NSFSC1662)。
This work was supported by the Sichuan Natural Science Foundation project(2023NSFSC1662), China.()
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