重症中暑(SHS)是一种高病死率疾病，因其发病机制不清，暂无针对性治疗措施。近期研究显示，SHS是在热打击基础上，继发全身炎症反应综合征，进而致多脏器功能衰竭的过程，而肠源性感染和内毒素血症可能是其发生发展的关键机制。我们前期研究中发现SHS动物存在肠道损伤现象，且肠道局部炎症和损伤程度与全身炎症反应和疾病严重程度密切相关，提示肠道在中暑的发生发展中有重要作用，但其具体分子机制尚不明确。高迁移率族蛋白B1(HMGB1)是脓毒症重要的炎性分子，我们在中暑患者血中也发现HMGB1明显升高，并可直接损伤肠上皮细胞。本项目拟在前期工作基础上，利用动物和细胞模型，围绕HMGB1及可能参与其表达和分泌的RAGE和TLR-4受体、JAK/STAT和p38 MAPK信号通路，通过基因敲除动物、RANi技术及降温和抗炎药物处理，从正反双向研究HMGB1在肠道损伤中的作用机制，为降低SHS病死率提供科学依据。

The high mortality of severe heatstroke (SHS) is dut to the unclear mechanisms that heat stress induces systemic inflammatory response syndrome and multiple organ dysfunction syndrome, so as to no specific treatment is available. Gut-derived endotoxin and pathogenic bacteria have been proposed to be an important causative factor of morbidity and death during heatstroke. Our previous works also found that heat stress induced elevation of intestinal permeability, bacterial translocation and the occurrence of endotoxemia, and that the degree of intestinal inflammatory response and injury was associated with systemic inflammatory response and disease severity, suggesting that intestine may play an important role in SHS. However, the molecular changes underlying heat stress-induced intestinal lesions have not yet been well characterized. High mobility group box 1 (HMGB1) is a key inflammatory factor in sepsis. Our studies also shown that HMGB1 increases obviously in heatstroke patients, and can directly damage intestinal epithelial cells. Based on above knowledgement,in this project the SHS animal model and heat-stressed intestinal epithelial cells will be used. The changes in HMGB1 and the molecules that probably regulating HMGB1 expression and secretion inculuding its receptors (RAGE and TLR-4) and signal molecules (JAK/STAT and p38 MAPK) will be detected. Moreover, HMGB1 knockout animal, RANi technology, intenstinal protection interventions(cooling treatment and anti-inflammatory medicine) will also be used to clarify the regulation mechanisms of HMGB1 expression and secretion to intestinal lesions in SHS from the pros and cons of two-way, so as to provided the experimental basis for reducing SHS mortality.