Nlrp3炎性小体信号途径介导劳力型热射病条件下横纹肌溶解症的作用机制

It’s well known that the morbidity of rhabdomyolysis (RM) is dramatically increased in exertional heat stroke (EHS) patients, which was attributed to the significantly increased fatality and deformity rates compared with the classic heatstroke (CHS) patients. However, the exact mechanism underlying the pathogenesis of RM under the circumstance of EHS has not yet been fully understood. Based on the more reasonable EHS animal model that we have successfully constructed in the previous studies, we have demonstrated for the first time that even though the EHS animal underwent much less thermal load before HS onset, the mortality of EHS animal was still much higher than that of the CHS animal. Further investigation attributed the relative higher mortality of EHS animal to the RM, because the extent of RM had negative relation with the survival time, and the EHS animals had much more higher incidence of RM in comparison with CHS animals. In previous studies, we have demonstrated that EHS could induce Nlrp3 inflammasome activation in skeletal muscle, and the level of Nlrp3 inflammasome activation had positive correlation with the extent of the damage of skeletal muscle. Therefore, we proposed our hypothesis that the activation Nlrp3 inflammasome/IL-1β signaling pathway of the skeletal muscle might expand inflammatory response, and thus play an essential role in the pathogenesis of RM following EHS onset. This study will manage to further investigate the molecular mechanism underlying the pathogenesis of RM which is mediated by activation of Nlrp3 inflammasome signaling pathway in EHS. Our research will manage to investigate the molecular mechanism of EHS inducing the activation of Nlrp3 inflammasome/ IL-1β signaling in the skeletal muscle, and its role on the development of RM from both in vivo and in vitro levels. The result of this research may help us better understand the pathophysiology mechanism of RM induced by EHS, and to find the new therapeutic and diagnostic target for the treatment and prevention of RM.

劳力型热射病患者横纹肌溶解症发病率高，显著增加病死率和病残率，但其具体发病机制目前尚不清楚。我们前期研究率先构建的劳力型热射病动物模型证实尽管劳力型热射病动物成模所需的热负荷相对更少，但死亡率显著高于经典型热射病动物，经典型热射病动物横纹肌溶解发病率显著低于劳力型热射病动物，横纹肌溶解严重程度与生存时间呈负相关，同时我们也证实劳力型热射病动物骨骼肌存在Nlrp3炎性小体/IL-1β信号途径激活，其活性的时程变化与骨骼肌损伤程度的时程变化一致。由此我们提出假说，劳力型热射病诱导Nlrp3炎性小体/IL-1β信号途径激活，扩大骨骼肌炎症反应，加重骨骼肌损伤，在劳力型热射病横纹肌溶解症的发病机制中起核心作用。因此我们拟进一步探究Nlrp3炎性小体及其相关信号途径介导劳力型热射病的横纹肌溶解症的分子机制，进一步阐明劳力型热射病条件下横纹肌溶解症的发病理论，探索更为有效的防治措施。

劳力型热射病（EHS）是重症中暑中最严重的一种类型，病死率高，救治难度大，而横纹肌溶解症（RM）是其高发且影响其预后的重要因素，而在此过程中骨骼肌细胞死亡的具体分子机制尚不明晰。申请人优化了EHS造模条件，获得与临床上病死率类似且高发RM的EHS小鼠模型，在此模型基础上，借助转录组测序进行生物信息学析，结果提示铁死亡（Ferroptosis）相关通路在EHS条件下的骨骼肌组织中上调。进一步体内和体外反向功能抑制实验提示铁死亡是EHS条件下RM发生进展的重要原因。抑制骨骼肌细胞铁死亡可明显减轻骨骼肌组织的过氧化脂质累积，改善EHS条件下RM的症状，并进一步减轻RM引起的肾功能损害。靶向抑制骨骼肌组织铁死亡可降低EHS小鼠24h内死亡率，且越早干预，其效果越好。在分子机制上，阐明了YAP/Tead1/Tead4/ACSL4轴在EHS条件下诱导骨骼肌发生铁死亡的作用和机制。本研究首次探索并证明ACSL4介导的铁死亡是EHS条件下RM发生进展的重要原因，这为临床上针对EHS患者开展精准治疗提供新思路。