Research progress on the potential mechanism of mesenchymal stem cells and exosomes in high altitude brain edema
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摘要:
近年来, 短期、长期居住在高海拔地区的人数不断增加，超过8 160万人生活在海拔≥2 500米的地区，而中国常居高原者超过1 000万，每年进入高原的人口超过2 000万。独特的高原气候引发了一系列高原相关性疾病，其中高原脑水肿(HACE)是最严重的疾病之一，如果不及时进行适当治疗，患者可能会在24 h内因脑疝死亡。然而, HACE发展的确切机制尚不完全清楚，使得HACE的防和治具有挑战性。间充质干细胞(MSC)及间充质干细胞外泌体(MSC-Exos)具有修复受损组织和细胞、抗氧化应激、抑制炎症反应、调节自噬等作用，有可能成为防治HACE的新型药物。本文结合国内外相关文献阐述高原脑水肿发病机制及MSC、MSC-Exos在其中可能发挥的作用，为MSC、MSC-Exos防治HACE提供理论依据。
Abstract:In recent years, the number of people living in short-term and long-term period in high-altitude has been continuously increasing, with over 81.6 million people living in areas with an altitude of ≥ 2, [KG*9]500 meters. In China, there are over 10 million people who frequently reside at high altitudes, and over 20 million people enter the plateau every year. The unique plateau climate has triggered a series of plateau related diseases, among which high altitude cerebral edema (HACE) is one of the most serious diseases. If patients are not treated promptly and appropriately, they may die from cerebral hernia within 24 hours. However, the exact mechanism of the development of HACE is not fully understood, which makes the clinical prevention and treatment of HACE challenging. Mesenchymal stem cells (MSC) and their exosomes (MSC-Exos) have the ability to repair damaged tissues and cells, resist oxidative stress, inhibit inflammatory reactions, and regulate autophagy, which may potentially become new drugs for preventing and treating HACE. This article elucidated the pathogenesis of high altitude brain edema and the potential roles of MSC and MSC-Exos based on relevant literature
at home and abroad, providing a theoretical basis for the prevention and treatment of HACE by MSC and MSC-Exos.
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肺结核是一种由结核分枝杆菌感染引起的慢性传染病，由于其发病率、传染率高，被称为世界上最致命的传染病杀手[1-2]。近年来，受到免疫缺陷病毒感染和耐药菌株增加的影响，肺结核的防治遇到了很多困难[3]。若1个或多个器官和组织发生衰竭，患者疾病会进展为重症肺结核，诱发大咳血等一系列并发症，极大威胁患者生命健康[4]。血清应激诱导蛋白2(Sestrin2)是Sestrin家族的重要成员，是一组维持氧化还原稳态所需的应激诱导蛋白，是抗氧化体系的重要成员，在机体缺氧、遗传物质损伤、氧化应激和内质网应激等情况下, Sestrin2的表达上调[5]。Sestrin2在细胞里可以与很多信号通路相互作用，调节细胞相关生物学功能能够防止其被氧化应激影响，且该蛋白和肝脏、心血管、呼吸系统等疾病的发病关系十分密切[6]。血清胎球蛋白A(Fetuin-A)是一种多功能蛋白，属于内源性抑制剂，可减少胰岛素受体酪氨酸激酶的分泌，在脂质代谢中具有促炎作用，诱导炎症反应[7]。但是关于血清Sestrin2、Fetuin-A水平与重症肺结核患者疾病转归关系的报道较少。本研究探讨血清Sestrin2、Fetuin-A水平变化与重症肺结核患者疾病转归的关系。
1. 资料与方法
1.1 一般资料
选取2020年12月—2022年12月收治的108例重症肺结核患者为研究对象，其中男68例，女40例; 年龄35~75岁，平均(60.36±9.54)岁; 体质量指数19~30 kg/m2, 平均(20.17±3.15) kg/m2。按照治疗结果将患者分为生存组(n=86) 和死亡组(n=22)。生存组年龄(60.16±9.54)岁，男56例，女30例，体质量指数(20.14±4.23) kg/m2, 吸烟史4例，饮酒史11例; 死亡组(60.67±9.46)岁，男12例，女10例，体质量指数(20.30±4.25) kg/m2, 吸烟史3例，饮酒史4例。2组年龄、性别、体质量指数、吸烟史、饮酒史等基本资料比较，差异无统计学意义(P>0.05)。纳入标准: ①符合重症肺结核的诊断标准[8]，形成3个肺野以上的肺部结核病灶，有空洞或长时间排菌，有明显结核病毒性症状以及红细胞沉降率增加者; ②无其他疾病呼吸系统者; ③患者均已成年且临床数据完整者; ④患者配合度高; ⑤患者及监护人签署同意书; ⑥由同一医师小组治疗，且治疗方案相同者。本研究经医院伦理委员会审核通过。排除标准: ①有其他恶性肿瘤者; ②严重器官功能障碍者; ③有酗酒史、吸毒史者; ④有其他传染性疾病者。
1.2 方法
1.2.1 血清Sestrin2、Fetuin-A水平检测
入院24 h内采集患者空腹状态下静脉血，经离心处理后，保留上层清液，采用酶联免疫吸附法检测Sestrin2、Fetuin-A水平(试剂盒由云克隆科技股份有限公司生产)。
1.2.2 急性生理学及慢性健康状况评分系统(APACHEⅡ)评分[9]
入院24 h内采用APACHE Ⅱ评分对患者病情严重程度予以评估，包括年龄(0~6分)、急性生理(0~48分)及慢性健康评分(0~10分)，分数与疾病严重程度呈正相关。
1.3 疾病转归
根据治疗30 d内存活情况将患者分为生存组和死亡组，判定死亡的标准: 心跳停止; 无自主呼吸，呼吸停止; 脑组织和脑细胞死亡，脑功能完全丧失，均可判为死亡。
1.4 统计学分析
采用软件SPSS 23.0对数据进行处理，符合正态分布的计量资料以(x±s)表示，组间比较行t检验; 计数资料采用[n(%)]表示，组间比较行χ2检验; 采用Logistic回归分析观察重症肺结核患者预后的影响因素; 采用受试者工作特征(ROC)曲线及曲线下面积(AUC)分析血清Sestrin2、Fetuin-A与重症肺结核患者疾病转归的关系。P＜0.05为差异有统计学意义。
2. 结果
2.1 2组血清Sestrin2、Fetuin-A水平比较
死亡组血清Sestrin2水平高于生存组，生存组血清Fetuin-A水平高于死亡组，差异有统计学意义(P＜0.05), 见表 1。
表 1 2组血清应激诱导蛋白2和胎球蛋白A水平比较(x±s)组别 n 应激诱导蛋白2/(ng/mL) 胎球蛋白A/(μg/mL) 生存组 86 10.67±2.95 392.36±38.82 死亡组 22 15.29±3.34* 332.15±36.79* 与生存组比较, * P＜0.05。 2.2 血清Sestrin2、Fetuin-A对重症肺结核疾病转归的预测价值
血清Sestrin2、Fetuin-A预测重症肺结核患者疾病转归的AUC分别为0.752、0.887, 两者联合预测的AUC为0.920, 见表 2、图 1。
表 2 血清应激诱导蛋白2和胎球蛋白A水平对重症肺结核患者疾病转归的预测价值检测指标 AUC 95%CI 截断值 特异度/% 灵敏度/% 应激诱导蛋白2 0.752 0.712~0.797 12.39 ng/mL 55.64 92.73 胎球蛋白A 0.887 0.842~0.937 350.67 μg/mL 65.57 92.73 联合预测 0.920 0.875~0.970 — 86.06 88.21 2.3 重症肺结核患者疾病转归的单因素分析
死亡组糖尿病史占比高于生存组，呼气流量峰值(PEF)、最大呼气中段流量(MMEF)、第1秒用力呼气容积(FEV1)水平、左心室射血分数(LVEF)低于生存组，差异有统计学意义(P＜0.05), 见表 3。
表 3 重症肺结核患者疾病转归的单因素分析指标 生存组(n=86) 死亡组(n=22) 糖尿病 13(15.12) 8(36.36)* 左心室射血分数/% 56.87±6.54 48.26±5.59* 呼气流量峰值/L 6.94±0.84 4.27±0.79* 最大呼气中段流量/% 2.95±0.39 1.58±0.25* 第1秒用力呼气容积/L 4.10±0.56 2.21±0.38* 与生存组比较, * P＜0.05。 2.4 重症肺结核患者疾病转归的多因素Logistic回归分析
本研究将重症肺结核患者的疾病转归作为因变量(生存=0、死亡=1), 将单因素分析有意义的指标及Sestrin2、Fetuin-A血清水平作为自变量进行多因素Logistic回归分析，结果显示，血清Sestrin2(OR=5.709, 95%CI: 1.993~16.355)、血清Fetuin-A(OR=4.826, 95%CI: 1.797~12.960)是重症肺结核疾病转归的危险因素(P＜0.05), 见表 4。
表 4 重症肺结核患者有关疾病转归的多因素Logistic回归分析变量 回归系数 标准误 Wald χ2 P OR(95%CI) 左心室射血分数 1.329 0.509 6.817 ＜0.001 3.777(1.393~10.243) 应激诱导蛋白2 1.742 0.537 10.523 ＜0.001 5.709(1.993~16.355) 胎球蛋白A 1.574 0.504 9.753 ＜0.001 4.826(1.797~12.960) 赋值: 左心室射血分数(≤50.00%=0, >50.00%=1); 应激诱导蛋白2(＜12.39 ng/mL=0, ≥12.39 ng/mL=1);
胎球蛋白A(＜350.67 μg/mL=1, ≥350.67 μg/mL=0)。3. 讨论
肺结核救治难度较大，有极高的病死率[10]。研究[11]报道，中国是结核病高负担国家之一，新发结核病病例超80万例，发病率为58/100 000, 肺结核防控与治疗工作仍面临挑战。如果患者不能得到及时处理，病变可能会导致病情延长及恶化，从而加重患者病情。当病情发展成重症肺结核时，患者器官组织会迅速出现功能衰竭，甚至危及生命。因此，早期判断患者与此疾病转归相关的特异性指标，对于早期诊断及预后评估非常重要。
Sestrin2为缺氧诱导基因95, 具有抗氧化功能，是人体各个系统种抗氧化防御机制的重要组成部分[12]。Sestrin2可与细胞内很多信号通路产生互相作用，并利用调控如凋亡、自噬、线粒体稳态、内质网应激等细胞生物学相关功能，保护细胞不会被氧化应激所影响，在多种呼吸代谢疾病中发挥重要作用[13-14]。既往研究[15]发现，哮喘与氧化应激密切相关, Sestrin2在哮喘急性发作中和急性发作后都有明显上升，并与FEV1呈正相关。在阻塞性睡眠呼吸暂停综合征患者尿液中亦检测出Sestrin2蛋白，且浓度水平较对照组高，以上研究均证实Sestrin2可作为呼吸系统方面疾病重要检测标志物，有助于治疗呼吸系统相关疾病。
本研究结果显示，死亡组血清Sestrin2水平高于生存组，提示血清Sestrin2水平在重症肺结核患者中表达上调，可作为患者疾病转归的指标，原因为重症肺结核造成的患者免疫低下，释放大量炎性因子, Sestrin2的表达上升显著，能够利用其内在的还原酶活性加速过氧化物氧化还原酶的再循环从而使氧化应激减轻，亦能够被Nrf2、P53、转录激活因子-1和FoxO等各种转录因子转录诱导，达到人体免受氧化应激影响的效果[16-18], 进而限制了器官发生进行性损伤。结果显示，血清Sestrin2预测重症肺结核患者疾病转归的AUC为0.752, 灵敏度为92.73%; 血清Sestrin2 ≥12.39 ng/mL是重症肺结核患者疾病转归的影响因素，提示检测血清Sestrin2水平可作为预测重症肺结核患者疾病转归事件的指标。Fetuin-A属于半胱氨酸蛋白酶抑制物超基因家族中一种多功能蛋白，与心血管疾病、自身免疫性疾病、肿瘤、感染等相关[19]。本研究结果显示，生存组血清Fetuin-A水平高于死亡组，且死亡组血清Fetuin-A水平低于生存组，提示血清Fetuin-A在重症肺结核患者中呈下降趋势，并影响患者疾病转归。人血清Fetuin-A是一种主要由肝脏分泌的糖蛋白，拥有丰富的生物功能，可以充当一种负向调节蛋白，对机体炎症反应起着抑制作用。
本研究结果显示，血清Fetuin-A浓度在重症肺结核疾病中表达下降，且死亡组Fetuin-A水平低于生存组，本研究与上述相关研究结果一致，提示Fetuin-A可能成为预测重症肺结核疾病转归的指标。结果显示，血清Fetuin-A预测重症肺结核患者化疗相关心脏毒性的AUC为0.887, 灵敏度为92.73%; 血清Fetuin-A＜350.67 mg/L是重症肺结核疾病转归的影响因素，表明Fetuin-A可作为预测重症肺结核疾病转归的辅助指标，且Fetuin-A低表达会使病死率增高。
综上所述，血清Sestrin2、Fetuin-A水平变化与重症肺结核的疾病转归密切相关，可作为评估重症肺结核的生物学指标，且两者联合预测的效能更高。本研究也存在一定不足: 研究范围和样本量小，未长期对患者疾病转归效果进行充分评估，无法全面了解患者的预后情况，因此还需要扩大样本量，延长观察时间以进一步确认研究效果。
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