热应激伴随炎症反应和氧化应激损伤，常造成多器官功能衰竭，细胞死亡是造成重要器官功能衰竭的主要原因之一。依赖于caspase-1激活的炎症性坏死（pyroptosis）在热应激损伤中的作用未见报道。我们的初步研究表明，热应激可以激活NLRP3炎症小体，进一步激活caspase-1。推测热应激通过激活NLRP3炎症小体而活化caspase-1，进而介导pyroptosis，引起热应激损伤。基于此，本研究主要应用NLRP3炎症小体相关的3种基因敲除小鼠及RAW 264.7细胞株，在体内外探讨NLRP3炎症小体在热应激损伤中的作用及可能机制，为基于NLRP3炎症小体的热应激损伤防治研究提供理论依据。

Heat stress, followed by inflammation and oxidative stress, offten induces multiple organ failure. Cell death is an important cause of organ failure. There is no report about the effect of pyroptosis, which depends on the activation of caspase-1, on the heat stress-induced injury. In our preliminary study, we found NLRP3 inflammasome was activated by heat stress. These results suggest that heat stress may induce pyroptosis by activating caspase-1 caused by NLRP3 inflammasome activation. In this project, we study the effect of NLRP3 inflammasome on heat stress-induced injury and as well the underlining mechanisms using NLRP3 inflammasome associated knockout mice and RAW 264.7 cell line. This will provide new ideas and methods for the treatment of heat stress-induced injury in clinic.

感染性并发症的患者更容易受到热应激性损伤的影响，但其潜在机制尚不清楚。最近的研究表明NLRP3炎症小体在中暑中起着重要的作用。在本课题中，我们应用腹腔巨噬细胞和小鼠热应激模型来阐明NLRP3炎症小体在因感染而加重的热应激损伤中的作用。研究发现，LPS复合热应激可以激活NLRP3炎症小体，IL-1β生成量明显增加。并且激活的NLRP3炎症小体参与热应激损伤，Nlrp3、ASC或Caspase-1基因敲除后，热应激损伤减轻，小鼠对热的耐受力明显增强，表现为敲除小鼠热应激时体温升高缓慢，较晚达到热射病标准，生存时间明显延长。NLRP3相关基因敲除的这一保护作用与IL-1β的释放减少有关，因为给予IL-1β中和抗体也能得到相似的结果，小鼠体温升高减缓，生存时间延长。因此，基于上述结果，我们得出结论：NLRP3炎症小体激活是感染加重热应激损伤的重要机制之一，NLRP3炎症小体可能是热应激损伤治疗的潜在靶点。