Department of Emergency, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Department of Emergency, Air Force Hospital of Eastern Theater Command, Nanjing, China.
Int J Hyperthermia. 2024;41(1):2378867. doi: 10.1080/02656736.2024.2378867. Epub 2024 Aug 8.
Exertional heatstroke (EHS) mainly occurs in healthy young people with rapid onset and high mortality. EHS immune disorders can cause systemic inflammatory responses and multiple organ failure; however, the underlying mechanisms remain unclear. As high mobility group box 1 (HMGB1) is a prototypical alarmin that activates inflammatory and immune responses, this study aimed to investigate the effect and mechanism of HMGB1 in the pathogenesis of EHS.
Peripheral blood mononuclear cell (PBMC) transcriptome sequencing of healthy volunteers, classical heatstroke patients, and EHS patients was performed. A mouse model of EHS was established and murine tissue damage was evaluated by H&E staining. HMGB1 localization and release were visualized using immunofluorescence staining. Human umbilical vein endothelial cells (HUVECs) and THP-1 cells were co-cultured to study the effects of HMGB1 on macrophages. A neutralizing anti-HMGB1 antibody was used to evaluate the efficacy of EHS treatment in mice.
Plasma and serum HMGB1 levels were significantly increased in EHS patients or mice. EHS-induced endothelial cell pyroptosis promoted HMGB1 release in mice. HMGB1 derived from endothelial cell pyroptosis enhanced macrophage pyroptosis, resulting in immune disorders under EHS conditions. Administration of anti-HMGB1 markedly alleviated tissue injury and systemic inflammatory responses after EHS.
The release of HMGB1 from pyroptotic endothelial cells after EHS promotes pyroptosis of macrophages and systemic inflammatory response, and HMGB1-neutralizing antibody therapy has good application prospects for EHS.
运动性中暑（EHS）主要发生于健康的年轻人，起病急骤，病死率高。EHS 可引起免疫功能紊乱，导致全身炎症反应和多器官功能衰竭，但发病机制尚不清楚。高迁移率族蛋白 B1（HMGB1）是一种典型的危险相关分子模式（DAMP），可激活炎症和免疫反应。本研究旨在探讨 HMGB1 在 EHS 发病机制中的作用及机制。
对健康志愿者、经典热射病患者和 EHS 患者的外周血单个核细胞（PBMC）转录组进行测序。建立 EHS 小鼠模型，通过 H&E 染色评估小鼠组织损伤。通过免疫荧光染色观察 HMGB1 的定位和释放。将人脐静脉内皮细胞（HUVEC）与 THP-1 细胞共培养，研究 HMGB1 对巨噬细胞的影响。用中和抗 HMGB1 抗体评估 EHS 治疗在小鼠中的疗效。
EHS 患者或小鼠的血浆和血清 HMGB1 水平明显升高。EHS 诱导的内皮细胞焦亡促进了小鼠 HMGB1 的释放。内皮细胞焦亡产生的 HMGB1 增强了巨噬细胞的焦亡，导致 EHS 条件下的免疫功能紊乱。EHS 后给予抗 HMGB1 可明显减轻组织损伤和全身炎症反应。
EHS 后来源于焦亡内皮细胞的 HMGB1 释放促进了巨噬细胞的焦亡和全身炎症反应，HMGB1 中和抗体治疗对 EHS 具有良好的应用前景。
