HMGB1/RAGE信号通路激活NLRP3炎症小体在COPD急性加重期中的作用及其机制研究

Acute exacerbation of COPD is the main cause lead to death , but the treatment effect is poor now in the world. In recent years，researcher found that HMGB1 and its membrane receptor RAGE were significantly increased in smoking patients with COPD. The activation of NLRP3 has also been found in patients COPD serum, while NF-κB can regulate the transcription of NLRP3 to participate in inflammatory responses. Activate NF-κB and NLRP3 can positive feedback and promote the generation of HMGB1 secretion. So we assume that HMGB1 / RAGE-NF-κB-NLRP3 this positive feedback loop play an important role in the acute aggravating period of COPD. This project is aim to test the expression of HMGB1 / RAGE, NF-κB and NLRP3 in COPD model in vivo and in vitro; Then increase or knock out of HMGB1 / RAGE, study its influence on regulation of the development of acute exacerbation of COPD; By intervening in the downstream NF-κB and NLRP3 to observe the changes of HMGB1, IL-1β and IL-8 and so on. This study will confirm HMGB1 / RAGE through NF-κB mediated NLRP3 inflammasome activation play an important role in the acute exacerbation of COPD progress, will help to elucidate the specific mechanism of acute aggravating period of COPD.

COPD急性加重期是COPD导致死亡的主要原因，但当前治疗效果欠佳。近年来发现在吸烟的COPD患者体内HMGB1与其膜受体RAGE明显增加。NLRP3的激活可见于COPD患者血清中，而NF-κB可调控NLRP3的转录参与炎症反应。活化的NF-κB及NLRP3炎症小体又可以正反馈促进HMGB1的产生和分泌。我们猜测HMGB1/RAGE-NF-κB-NLRP3这个正反馈环路的激活在COPD急性加重期发挥重要作用。本项目拟通过COPD急性加重期体内外模型检测HMGB1/RAGE、NF-κB及NLRP3的表达变化；增加或敲除HMGB1/RAGE，研究对COPD急性加重期发展的影响；干预下游NF-κB及NLRP3观察对HMGB1及IL-1β、IL-8等的影响。本研究将证实HMGB1/RAGE通过NF-κB介导的NLRP3炎症小体激活在COPD急性加重期进展中发挥重要作用，为临床治疗提供理论基础。

COPD是以进行性气流受限和气道的炎症为特征的疾病，尤其是COPD急性加重期治疗效果欠佳。近年来发现在吸烟的COPD患者体内HMGB1明显增加。NLRP3的激活可见于COPD患者血清中， 而NF-κB可调控NLRP3的转录参与炎症反应。活化的NF-κB及NLRP3炎症小体又可以正反馈促进 HMGB1的产生和分泌。我们提出假设HMGB1-NF-κB-NLRP3这个正反馈环路的激活在COPD急性加重期发挥重要作用。本研究发现在急性COPD患者血清、小鼠AECOPD模型肺组织、小鼠巨噬细胞RAW264.7和人原代诱导巨噬细胞系THP-1中，NF-κB和NLRP3活化、HMGB1的表达均增加。在细胞水平，我们发现miR-223可以靶向抑制NLRP3和PARP-1，而PARP-1可以抑制NF-κB，从而抑制HMGB1的表达；在小鼠AECOPD模型肺组织和肺泡灌洗液中，HMGB1的表达增加，给与miR-223的类似物可以抑制HMGB1和NLRP3的表达，从而降低 IL-1β的表达，减轻肺部炎症；相反，给与miR-223的拮抗物可以增加HMGB1和NLRP3的表达，从而增加 IL-1β的表达，加重肺部炎症。因此我们提出miR-223通过抑制NF-KB/NLRP3/HMGB1正反馈信号环路，减轻AECOPD患者肺部炎症。本研究将将为阐明COPD急性加重期的具体机制提供理论依据并且为临床治疗带来新的思路。