深空探测背景下登月宇航员脑血管疾病的风险、机制与防控策略

Risks, mechanisms, and prevention strategies for cerebrovascular diseases in lunar astronauts under deep

摘要

随着人类深空探测任务步入实质阶段，宇航员的健康安全保障成为决定任务成败的关键。脑血管系统作为维持脑功能的核心，其结构与功能对环境变化高度敏感。脑血管疾病是微重力、高能辐射等深空环境引发的典型后果之一，已成为国际空间医学关注的前沿难题。根据载人空间任务实践，当前研究仍存在登月环境实验数据匮乏、低剂量辐射损伤阈值不明等核心挑战。明确深空环境对脑血管的影响机制及多因素协同作用，总结登月宇航员脑血管疾病的关键危险因素、病理机制与监测预警技术进展，剖析深空环境与脑血管损伤的交互机制及个体化防控路径，可为未来中国登月宇航员脑血管健康防控提供理论与实践依据，推动相关医学研究、技术创新及国际协同发展。

Abstract

As human deep space exploration enters a practical phase, ensuring astronaut health and safety has become a critical determinant of mission success. The cerebrovascular system, essential for maintaining brain function, is highly sensitive to environmental changes. Cerebrovascular diseases represent one of the characteristic adverse effects of deep space conditions such as microgravity and high-energy radiation, and have emerged as a frontier challenge in space medicine. Based on experiences from manned space missions, major research challenges persist, particularly the lack of experimental data specific to the lunar environment and the unclear threshold for low-dose radiation-induced injury. Elucidating the mechanisms and multifactorial interactions by which deep space environments impact cerebrovascular structure and function, and summarizing the key risk factors, pathological processes, and recent advances in monitoring and early-warning technologies for cerebrovascular diseases in lunar astronauts, and of crucial importance. A comprehensive understanding of the interplay between deep space environmental stressors and cerebrovascular injury, as well as the development of personalized prevention and intervention strategies, will provide both theoretical and practical foundations for safeguarding cerebrovascular health in future Chinese deep space missions, while promoting progress in related biomedical research, technological innovation, and international collaboration.

Graphical abstract

关键词

深空探测 / 登月宇航员 / 脑血管疾病 / 微重力 / 空间医学

Key words

deep space exploration / lunar astronauts / cerebrovascular diseases / microgravity / space medicine

随着深空探测技术的突破，载人登月从阿波罗时代的短期探索迈向长期驻留与常态化任务，如美国国家航空航天局(National Aeronautics and Space Administration，NASA)阿尔忒弥斯计划和中国载人登月工程^[1]。与低地轨道(low Earth orbit，LEO)任务[如国际空间站(International Space Station，ISS)]相比，登月任务面临两大独特环境挑战：一是超越范艾伦辐射带的深空辐射环境，银河宇宙射线(galactic cosmic ray，GCR)中的高电荷高能量(high-charge and high-energy particle，HZE)粒子(如铁、碳离子)占比显著升高，缺乏地球磁场的有效屏蔽^[2]；二是月面0.16 g的部分重力环境，虽不同于轨道微重力(0 g)，但仍打破了地球1 g环境下脑血管的重力依赖性调节稳态^[3-4]。

脑血管系统作为维持脑功能的核心，其结构与功能对环境变化高度敏感。太空环境可诱导心血管系统发生“类衰老”损伤(如动脉僵硬、内皮功能障碍)^[5-7]，而脑血管作为心血管系统的特殊分支，更易因脑血流自动调节异常、血脑屏障(blood-brain barrier，BBB)损伤而引发缺血性卒中、脑小血管病等并发症^[8-10]。在参与阿波罗任务(1968至1972年)的宇航员中虽未观察到急性脑血管事件，但随访数据^[11]显示登月宇航员晚年脑血管疾病发病率有升高趋势，提示长期潜在风险。因此，系统解析登月环境下脑血管疾病的风险来源、病理机制及防控策略，是保障长期载人登月任务安全的关键科学问题。

1 登月宇航员脑血管疾病的核心风险来源

1.1 深空辐射

深空辐射是登月宇航员脑血管疾病风险的主导因素之一，其危害源于GCR和太阳质子事件(solar proton event，SPE)引起的低剂量-高线性能量转移(linear energy transfer，LET)粒子辐射的长期潜伏性，虽然单次剂量相对较低[通常<0.5戈瑞(Gray，Gy)]，但高LET粒子在组织中产生密集的离子化轨迹，会导致低剂量-高LET的特殊生物效应^[12]。登月任务中宇航员累计辐射剂量为0.1~0.5希沃特(Sievert，Sv)，虽低于火星任务，但高LET粒子占比超20%，因此登月任务中辐射所带来的脑血管损伤风险远超地面X射线、γ射线等低LET辐射^[12-14]。流行病学数据^[15]显示切尔诺贝利事故清理者在低剂量0.15 Gy时脑血管疾病的发生风险已显著升高。广岛和长崎的队列研究^[16]也证实剂量≥0.5 Gy时缺血性脑血管疾病的超额相对风险达1.2~1.8，且HZE粒子(如⁵⁶Fe、¹²C)的相对生物效应是γ射线的5~10倍，实际生物等效剂量更高，可能突破损伤阈值^[17]。与LEO任务中以质子为主(HZE粒子占比<5%)不同，登月任务中GCR的HZE粒子穿透性强，可直接作用于脑内大、小血管，即使剂量低至0.2 Gy也会导致脑动脉内皮细胞DNA持续损伤和线粒体功能障碍，且修复效率比质子低40%；而质子剂量≥0.8 Gy时则会抑制血管内皮修复、诱导脑内血管生成障碍^[18-19]，高LET致密电离HZE粒子穿过细胞时，会对大分子产生直接和间接的细胞效应。活细胞吸收电离辐射后，会直接破坏原子结构，引发化学和生物学变化；同时，还会通过以下2种间接方式产生影响：一是导致细胞内水发生辐射分解，二是刺激氧化酶和内皮型一氧化氮合酶(endothelial nitric oxide synthase，eNOS)生成活性化学物质。此外，电离辐射还可能破坏线粒体功能，这一过程对短期和长期效应均有重要作用，最终导致脂质、蛋白质、核DNA(nuclear DNA，nDNA)和线粒体DNA(mitochondrial DNA，mtDNA)发生持续性改变(图1)。

1.2 微重力

在ISS任务中，微重力可致宇航员头部静脉血流停滞、压力升高及血管扩张，这是脑静脉血栓形成的核心病理机制；颈内静脉作为颅内静脉血回流主通路，其血流异常会进一步加剧该风险。Marshall-Goebel等^[20]的研究显示：11名ISS任务人员中6名存在颈内静脉血流停滞/逆转，2名发生闭塞性血栓。月面0.16 g重力环境虽较微重力存在部分重力恢复，但无法彻底逆转头部体液聚集现象^[21]。部分重力恢复状态下头部血管(如颈内静脉、门静脉)横截面积仍较地面环境增加30%~45%，据此推测月面环境中宇航员颅内静脉压仍维持于地面水平之上，且血流速度减慢状态持续存在，类比ISS数据推算其脑静脉血栓风险较地面人群升高5~10倍^[22-29]。月面0.16 g重力还会引发脑血管调节的“非稳态应激”——虽能部分缓解微重力“去负荷”效应，却无法复现地球1 g环境下的脑血管生理稳态^[6]。首先，月面头部-足部静水压梯度仅为地球的1/6，导致血液向胸腔-头部重分布，颅内压升高5~8 mmHg (1 mmHg=0.133 kPa)，诱发脑小血管被动扩张及血流自动调节范围缩小(地球1 g环境下脑血管依赖“重力-压力反射”维持稳定，直立时脑灌注压需较卧位高10~15 mmHg)^[25-27]。其次，月面舱外活动所需的4.3磅力每平方英寸(pounds per square inch，psi；1 psi=6.895 kPa)航天服会额外升高胸内压、降低脑静脉回流，叠加部分重力下心脏每搏量较地面降低15%~20%，易引发脑灌注不足^[28-29]。动物实验^[30]表明：小鼠暴露于0.16 g重力环境30 d后，脑微血管内皮紧密连接蛋白(如Occludin、Claudin-5)的表达量下降30%，血脑屏障通透性显著增加，血清白蛋白漏入脑组织量达地面水平的2倍，为炎症因子浸润及后续脑损伤奠定了病理基础。此外，长期暴露于微重力或月面重力环境还会诱导宇航员脑血管结构适应性重构：Arbeille等^[5]及Hughson等^[7]的研究均显示ISS宇航员在执行4~6个月任务后，颈动脉内中膜厚度增加且血管僵硬度升高，此类结构改变显著降低脑血管对血流波动的调节能力，叠加月面任务中“舱内-月面转换”等体位变化，易诱发脑灌注不足或局部血流紊乱，间接升高缺血性脑卒中风险。而小鼠暴露于0.16 g重力环境30 d后出现的类似动脉粥样硬化早期改变，如颈动脉内中膜厚度增加0.05~0.08 mm、大脑中动脉弹性模量升高25%，进一步佐证了脑血管损伤的普遍性^[31]。

1.3 任务相关应激

任务相关应激则通过“叠加效应”进一步加剧脑血管损伤，主要体现在舱外活动的生理负荷与心理应激、睡眠剥夺2方面。月面舱外活动单次持续4~6 h，宇航员需在舱外服约束下完成重物搬运、设备安装等高强度活动，心率可达120~150次/min，脑氧耗量增加50%，而脑血流因血管调节滞后易出现“供需失衡”，诱发短暂性脑缺血发作^[32]。同时，登月任务中宇航员面临月面尘暴、设备故障等极端环境不确定性，焦虑评分较ISS任务中的高，且睡眠周期受光照周期紊乱影响，睡眠效率降低，长期应激会激活交感神经-肾素-血管紧张素系统(renin-angiotensin-aldosterone system，RAAS)，导致脑小血管收缩痉挛、血压昼夜节律紊乱，进一步增加脑出血风险^[33]。

2 登月环境诱导脑血管疾病的病理机制

登月环境对脑血管的损伤是多靶点、多通路的复杂过程，核心机制可分为辐射特异性机制、重力依赖性机制及二者的协同作用，最终通过“内皮损伤-炎症激活-代谢紊乱”的级联反应诱发脑血管疾病。

2.1 辐射特异性机制

深空辐射以脑血管内皮细胞为核心损伤靶点，通过直接DNA损伤与间接氧化应激，从分子到细胞层面引发多维度破坏。在内皮细胞衰老与功能衰竭方面，HZE粒子(如⁵⁶Fe)因其高LET特性，会在脑微血管内皮细胞内形成“密集电离轨迹”，导致双链DNA断裂(double-strand break，DSB)数量是γ射线的3倍，且修复错误率升高^{[17, 34]}；未修复的DSB会激活p53-p21通路，诱导内皮细胞早衰，既能造成功能改变[如eNOS活性降低40%、NO生成减少，导致血管舒张障碍、内皮素-1(endothelin-1，ET-1)表达升高2倍，进一步引起血管收缩痉挛、衰老内皮细胞分泌的基质金属蛋白酶(matrix metalloproteinase，MMP)-2和MMP-9增加]，也可引发结构改变(降解血管基底膜，使脑微血管壁变薄、脆性增加，易破裂出血)^{[19, 35-37]}。在氧化应激与线粒体功能障碍方面，辐射会诱导脑内活性氧(reactive oxygen species，ROS)大量生成，内皮细胞中辐射激活的黄嘌呤氧化酶(xanthine oxidase，XO)使ROS生成增加3倍^[38]，且超氧化物歧化酶(superoxide dismutase，SOD)活性降低致抗氧化系统失衡，神经胶质细胞中HZE粒子照射后星形胶质细胞会释放ROS和促炎性细胞因子[如白细胞介素-6(interleukin-6，IL-6)、肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)]，进一步加重血管内皮氧化损伤^[39-40]。ROS过量积累会导致线粒体膜电位下降、呼吸链复合体IV活性降低、三磷酸腺苷(adenosine triphosphate，ATP)生成减少，最终引发脑微血管内皮细胞凋亡^[41]。在动脉粥样硬化加速与血栓形成方面，辐射通过“内皮损伤-脂质沉积-炎症浸润”经典通路起作用，各种损伤诱因(如血流剪切应力改变、氧化应激、炎症因子)激活内皮细胞的核因子-κB(nuclear factor-kappa B，NF‑κB)通路，促使细胞间黏附分子-1(intercellular adhesion molecule-1，ICAM-1)、血管细胞黏附分子-1(vascular cell adhesion molecule-1，VCAM-1)、E选择素(E-selectin)、P选择素(P-selectin)等黏附分子表达升高^[41-43]；单核细胞黏附并迁移至血管内皮下分化为巨噬细胞，吞噬氧化低密度脂蛋白(oxidized low-density lipoprotein，ox-LDL)形成泡沫细胞^[43-44]，同时HZE粒子激活转化生长因子-β(transforming growth factor-β，TGF-β)通路，促进血管平滑肌细胞(vascular smooth muscle cell，VSMC)增殖并迁移至内膜分泌胶原纤维形成纤维斑块，斑块破裂后暴露的胶原会激活血小板形成血栓，阻塞脑动脉，诱发缺血性卒中^[45-46]。

2.2 重力依赖性机制

月面0.16 g部分重力则通过“血流动力学重构”与“血管适应性异常”，破坏脑血管稳态。在脑血流自动调节(cerebrovascular reactivity，CVR)功能受损方面，地球1 g环境下脑血管依靠压力反射和化学反射(如CO₂敏感性)维持脑血流稳定^[47]，血压波动时脑小动脉通过收缩/舒张调节阻力，使脑血流变异率<10%^[48]；而在月面部分重力下，颈动脉窦压力感受器因重力负荷减少“脱敏”，对血压变化的反应延迟时间从0.5 s延长至1.2 s，且长期暴露后脑动脉对CO₂的舒张反应降低30%，当宇航员进行舱外活动等高代谢活动时，CO₂潴留无法有效扩张脑血管，易导致脑缺氧^[49-51]。神经血管单元由内皮细胞、星形胶质细胞、神经元组成，是维持脑代谢稳态的核心结构。在脑内代谢紊乱与神经血管单元(neurovascular unit，NVU)破坏方面，在月面部分重力下，脑微血管内皮细胞的葡萄糖转运体-1(glucose transporter-1，GLUT-1)表达降低25%，导致脑葡萄糖摄取减少、神经元能量供应不足，同时星形胶质细胞的水通道蛋白4(aquaporin 4，AQP4)表达升高，引发脑组织水肿，进一步压迫脑微血管并加重脑灌注不足^[52-54]。

2.3 损伤叠加-修复抑制

深空辐射与月面部分重力还会通过“损伤叠加-修复抑制”产生1+1>2的协同效应，进一步放大脑血管疾病风险。一是辐射削弱重力适应性修复，部分重力诱导的脑动脉壁增厚本可通过内皮修复机制缓解，但辐射导致的内皮细胞衰老使修复能力下降50%，导致血管结构异常持续存在^[55]；二是重力紊乱加剧辐射氧化损伤，部分重力下脑血流较地面降低15%，导致ROS清除效率下降，叠加辐射诱导的ROS生成增加，使脑内氧化应激水平升高2倍，加速BBB损伤^{[55, 56]}；三是共同激活RAAS，辐射(通过氧化应激)和部分重力(通过血流动力学应激)均能激活肾素-血管紧张素-醛固酮系统，使血管紧张素II(angiotensin II，Ang II)表达升高，进一步收缩脑小血管、促进VSMC增殖，加速动脉粥样硬化进程^[55]。

3 登月宇航员脑血管疾病的防控策略

针对登月环境特殊性，脑血管疾病防控需依托“工程防护-生理干预-营养支持-监测预警”多维度策略，围绕“降低辐射暴露、恢复脑血管调节功能、抑制病理损伤通路”核心目标展开。

3.1 工程防护

在工程防护层面，重点构建“辐射-重力”双重屏障。深空辐射防护采用“分层屏蔽+头部强化+时间规避”方案，舱体使用含氢量14%的聚乙烯材料(对HZE粒子屏蔽效率比铝高30%，还能减少中子次级辐射)^[56-57]，宇航服头盔内衬添加0.5 cm厚硼化聚乙烯(降低脑区HZE粒子剂量率25%)^[58]，并选择太阳极小期执行任务(此时GCR剂量率降低40%)^[59]。

3.2 运动干预

基于ISS长期任务的运动对策经验，可将其转化为针对个体的脑血管功能维护方案。首先，借鉴ISS的“预飞‑在轨‑后飞”三阶段模式，依据航天员的体能基线和任务负荷，制订个体化的阻力训练[如高级抗阻训练设备(advanced resistive exercise device，ARED)与有氧(跑步机/自行车)]配比，确保每周6~7 d、每日约2.5 h的总量，并通过心率胸带和功率记录实时监测运动强度，以实现负荷的渐进式提升^[60-62]。其次，利用ISS期间收集的血流动力学和心肺指标[如最大摄氧量(maximal oxygen uptake，VO₂max)、动脉刚度]对训练效果进行量化评估，结合航天员的年龄、性别和基因背景进行个体化调节。研究^[63]表明：持续的阻力与有氧训练能够降低微血管僵硬、改善视网膜血管结构，进而提升全脑血管弹性和血流调节能力。在缺血性脑卒中模型中，类似的运动干预还能促进血管生成、神经再生，强化神经血管单元的完整性^[64]。因此，将ISS的高强度、个体化、数据驱动的运动方案与临床脑血管健康目标相结合，可为航天员及地面人群提供科学、可持续的脑血管功能维护路径。

3.3 营养支持

基于ISS长期任务的营养实验经验，可将其关键要素转化为个体化饮食方案，以维持和保护脑血管功能。首先，ISS营养监测表明在失重环境下通过实时评估体成分和代谢指标，及时调整能量、蛋白质及液体摄入，可防止体脂、肌肉和体液失衡，这为地面人群提供了“动态营养调节”模型^[65]。其次，太空任务中发现的盐分保留与交感神经激活提示，适度控制钠摄入、保证足够的钾、镁以及抗氧化微量元素(维生素C/E、硒)有助于维持血管内皮稳态，降低血压波动和血管硬化风险^[66]。此外，深空任务对大脑健康的研究^[67]强调肠‑脑轴的重要性，针对性补充富含ω‑3多不饱和脂肪酸、膳食纤维和益生元，可调节肠道菌群，抑制神经炎症，提升认知与血管调节功能。最后，ISS食物系统的限制(有限的储存空间、缺乏热水)提示应研发高营养密度、低体积、易保存的复合配方(如脱水蔬果粉、富含多酚的即食胶囊)，这些产品在个体化配比后能够满足不同代谢需求，同时提供足量的抗炎与血管保护营养素^[68]。综合上述要点，构建的个体化饮食方案应包括：1)基于体成分和代谢监测的动态能量/蛋白质调节；2)严格的钠‑钾平衡与抗氧化微量元素补充；3)针对肠‑脑轴的ω‑3与益生元摄入；4)使用高密度、易保存的太空级营养配方，实现全天候、精准的脑血管保护。

3.4 监测预警

在轨道平台利用经颅多普勒(transcranial doppler，TCD)实时测量大脑中动脉平均血流速度(mean cerebral arterial velocity，MCAV)，并通过可穿戴汗液传感器连续监测氧化应激标志物8‑异前列腺素等ROS代谢产物；同时在地面定期进行脑部MRI、颈动脉超声等结构与功能随访，将轨道数据通过安全卫星链路上传至地面中心，结合机器学习风险模型进行多模态融合分析，形成“在轨‑地面联动”动态监测体系，有助于实现脑卒中风险的早期预警并指导个体化干预措施^[69-70]。

4 结语与展望

当前登月宇航员脑血管疾病研究仍面临三大核心挑战：第一，登月环境的直接实验数据匮乏，现有研究多基于地面模拟或近地轨道任务，无法完全复现月面0.16 g重力环境与深空辐射的协同效应；第二，低剂量深空辐射的脑血管损伤阈值尚不明确，需通过更多动物实验(如恒河猴登月环境模拟)及长期人群随访(如阿尔忒弥斯计划宇航员队列)进一步验证；第三，防控策略的轻量化与长效性不足，例如人工重力系统的体积适配性、营养补充剂的长期安全性仍需优化。未来研究可聚焦三大方向：一是开发“月面脑血管模拟装置”，精准复现月面环境，解析辐射-重力协同作用机制；二是研发“多功能脑血管保护制剂”，实现抗氧化、抗辐射、改善脑血流的多靶点防护；三是建立“个体化脑血管风险预测模型”，结合宇航员的遗传背景[如载脂蛋白E(apolipoprotein E，APOE)多态性]和任务暴露参数，实现精准防控。通过“机制解析-策略研发-监测预警”的全链条突破，为长期执行载人登月任务的宇航员脑血管安全提供坚实保障。

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基金资助

国家自然科学基金项目(82471364)

湖南省重大基础研究项目(2024JC0004)

江西省卫生健康委员会科技创新重点项目(2025ZD003)

长沙市“揭榜挂帅”重大科技项目(kq2301008)

中南大学前沿交叉项目(2023QYJC011┫。This work was supported by the National Natural Science Foundation ┣82471364)

the Major Basic Research Projects of Hunan Province(2024JC0004)

the Jiangxi Provincial Health Commission Key Innovation Project(2025ZD003)

the Major Science and Technology Projects of Changsha(kq2301008)

the Central South University Research Programme of Advanced Interdisciplinary Studies(2023QYJC011)

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