Yuan Rui, Wang Lu, Deng Zi-Hui, Yang Meng-Meng, Zhao Yan, Hu Jie, Zhang Yu, Li Yun, Liu Meng, Liu Shi-Fei, Zhou Fei-Hu, Kang Hong-Jun
Department of Critical Care Medicine, Chinese PLA General Hospital, Beijing 100853, China.
Department of Biochemistry, Graduate School of Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China.
Curr Stem Cell Res Ther. 2023;18(3):401-409. doi: 10.2174/1574888X17666220511144254.
Heatstroke (HS) is a serious disease caused by central nervous system (CNS) injuries, such as delirium, convulsion, and coma. Currently, mesenchymal stem cells (MSCs) have demonstrated novel neuroprotective effects; therefore, this research explores the neuroprotective effects and mechanisms of MSCs against HS injury.
HS rat models were induced in a 40°C and 65% humidity environment until the rectal temperature reached 42°C. The verified HS injury model rats were divided into the HS and MSCs-treated groups. Each rat in the treated group was infused with 1x10 MSCs suspended in 0.3 ml physiological saline via the tail vein. The HS- or MSCs-treated rats were further divided into early-stage (3d) and late-stage (28d). HS rat models were induced by a high-temperature and high-humidity environment at a specific time, the mortality was analyzed, and an automatic biochemical analyzer measured levels of liver and kidney function indicators in the blood. The neurons' morphologic changes were observed through Nissl staining, and neurological deficit scores were performed. Moreover, the levels of inflammatory factors in brain tissue were measured using a multi-cytokine detection platform, and the expression of BDNF, phosphorylated TrkB and P38 were detected by the Western Bolt.
MSCs injection significantly reduced mortality and alleviated liver and kidney function. Moreover, the neurological deficit and neuronic edema of the hippocampus caused by HS at 3d and 28d were significantly ameliorated by MSCs administration. Specifically, the injection of MSCs inhibited high levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and IL-17A caused by HS but elevated the levels of IL-10 and IL-13 in the early period (3d); while in the later period (28d), MSCs significantly increased the levels of IL-10 and IL-13 continuously and inhibited the high level of IL-17A. Furthermore, MSCs injection increased the expressions of BDNF and phosphorylated TrkB (BDNF receptor), meanwhile inhibiting the expression of phosphorylated P38 (inflammatory factor) in the brains of HS rats in the early period (3d) but had no significant influence on the later period (28d).
These results suggested that MSCs injection may provide therapeutic effects for HS in rats by improving liver and kidney function and reducing CNS damage. Moreover, MSCs injection inhibited the brain inflammatory response of HS rats, and the BDNF-TrkB and P38/MAPK signal pathways may be involved, providing a potential mechanism for HS therapy by MSCs administration.
中暑（HS）是一种由中枢神经系统（CNS）损伤引起的严重疾病，如谵妄、抽搐和昏迷。目前，间充质干细胞（MSCs）已显示出新型神经保护作用；因此，本研究探讨了MSCs对中暑损伤的神经保护作用及机制。
在40°C和65%湿度环境中诱导建立中暑大鼠模型，直至直肠温度达到42°C。将经验证的中暑损伤模型大鼠分为中暑组和间充质干细胞治疗组。治疗组的每只大鼠通过尾静脉注入悬浮于0.3 ml生理盐水中的1×10间充质干细胞。将中暑或间充质干细胞治疗的大鼠进一步分为早期（3天）和晚期（28天）。在特定时间通过高温高湿环境诱导建立中暑大鼠模型，分析死亡率，并使用自动生化分析仪检测血液中肝肾功能指标水平。通过尼氏染色观察神经元形态变化，并进行神经功能缺损评分。此外，使用多细胞因子检测平台测量脑组织中炎症因子水平，通过蛋白质免疫印迹法检测脑源性神经营养因子（BDNF）、磷酸化酪氨酸激酶B（TrkB）和P38的表达。
注射间充质干细胞显著降低了死亡率，减轻了肝肾功能损伤。此外，间充质干细胞给药显著改善了中暑在3天和28天引起的神经功能缺损和海马神经元水肿。具体而言，注射间充质干细胞抑制了中暑引起的高水平白细胞介素（IL）-1β、IL-6、肿瘤坏死因子-α（TNF-α）和IL-17A，但在早期（3天）提高了IL-10和IL-13的水平；而在后期（28天），间充质干细胞持续显著提高IL-10和IL-13的水平，并抑制了IL-17A的高水平。此外，注射间充质干细胞增加了BDNF和磷酸化TrkB（BDNF受体）的表达，同时在早期（3天）抑制了中暑大鼠脑中磷酸化P38（炎症因子）的表达，但在后期（28天）没有显著影响。
这些结果表明，注射间充质干细胞可能通过改善肝肾功能和减少中枢神经系统损伤为大鼠中暑提供治疗作用。此外，注射间充质干细胞抑制了中暑大鼠的脑部炎症反应，可能涉及BDNF-TrkB和P38/丝裂原活化蛋白激酶信号通路，为间充质干细胞给药治疗中暑提供了潜在机制。
