脓毒症急性肺损伤（ALI）是导致脓毒症患者高死亡率的重要原因。申请者前期研究发现:HSF1基因敲除小鼠较野生型小鼠脓毒症ALI症状加重，血清及肺泡灌洗液IL-1β和IL-18增高，肺脏NLRP3炎症小体表达增加。RAW264.7细胞过表达HSF1可以抑制内毒素诱导的NLRP3炎症小体活化。据此本项目提出如下假说：HSF1抑制NLRP3炎症小体激活保护脓毒症ALI,其机制可能为：①直接结合并抑制NLRP3炎症小体基因表达；②上调HSP70、TAX1BP1表达而抑制NF-κB信号通路介导的NLRP3、IL-1β生成；③上调HSP90、SGT1表达，抑制NLRP3翻译后活化。针对上述假说，本项目拟采用HSF1基因敲除小鼠制备脓毒症模型，从整体、细胞及分子水平揭示HSF1通过转录及转录后修饰抑制NLRP3炎症小体激活保护脓毒症ALI的机制，为脓毒症ALI以及脓毒症的干预和治疗找到新的突破口。

The acute lung injury (ALI) is one of the most common complications of sepsis，which results in high mortality of patients. It is demonstrated in our experiments that HSF1 knock out mice suffered more serious sepsis induced ALI than wild ones. IL-1β and IL-18 were increased higher in peripheral blood and bronchoalveolar lavage fluid, and the pulmonary expression of NLRP3 inflammasome was also increased greater compared with the wild type mice. RAW264.7 cells over-expressing HSF1 can inhibit the NLRP3 inflammasome activation induced by LPS. Combined our animal, cellular and molecular experiments, it is hypothesized that HSF1 can protect the ALI induced by sepsis in the following mechanisms: Firstly, HSF1 can directly bind the promoter of NLRP3 inflammasome genes and inhibit their expression. Secondly, HSF1 can inhibit NLRP3，IL-1βexpression via a NF-κB signal pathway inhibition caused by increased HSP70 and TAX1BP1. And finally, HSF1 can inhibit the post-translation activation of NLRP3 via increasing the ubiquitination enzyme complex composed of increased HSP90 and STG1. We plan to prove our hypothesis via preparing a septic model using HSF1 knockout mice, then investigating the protective effect of HSF1 on the priming and activation of NLRP3 in sepsis-induced ALI by animal, cellular and molecular experiments. It is expected that this project will elucidate the cellular and molecular mechanisms by which HSF1 alleviates sepsis induced ALI from a completely new angle of viewpoint and provide new targets and experimental evidences for intervention and treatment of both sepsis-induced ALI and sepsis patients .