NLRP3/ASC-mediated alveolar macrophage pyroptosis enhances HMGB1 secretion in acute lung injury induced by cardiopulmonary bypass
NLRP3/ASC-mediated alveolar macrophage pyroptosis enhances HMGB1 secretion in acute lung injury induced by cardiopulmonary bypass
复制标题
NLRP3/ASC介导的肺泡巨噬细胞焦亡增强体外循环所致急性肺损伤中HMGB1的分泌
DOI：
10.1038/s41374-018-0073-0
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发表时间：
2018-08-01
影响因子：
5
通讯作者：
Wang, Xiangrui
中科院分区：
文献类型：
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作者：
Hou, Lei;Yang, Zhongwei;Wang, Xiangrui
我们之前的研究表明，体外循环（CPB）诱导的急性肺损伤（ALI）大鼠中存在高水平的HMGB1，中和高迁移率组盒1（HMGB1）可降低CPB诱导的ALI。然而，CPB增加HMGB1分泌的机制尚不清楚。最近的研究表明，炎症小体介导的细胞热亡促进HMGB1的分泌。本研究旨在探讨炎症小体介导的焦亡与HMGB1在cpb相关性ALI中的关系。我们采用氧葡萄糖剥夺（OGD）诱导的肺泡巨噬细胞（AM） NR8383焦亡法检测HMGB1的分泌。我们发现，OGD显著增加了caspase-1切割的p10、IL-1 β和ASC的表达水平、caspase-1活性和焦亡AM的频率，并促进了HMGB1的细胞质运输和分泌，而AM中ASC沉默或格列本脲（一种Nlrp3抑制剂）预处理可显著减轻这些作用。CPB还增加了Nlrp3、ASC、caspase-1 P10和IL-1 β的表达水平，并增加了实验大鼠肺中AM焦亡的百分比，同时增加了血清和支气管肺泡灌洗液（BALF） HMGB1的水平。格列本脲治疗可显著减轻cpb增加的大鼠ASC、caspase-1 p10和IL-1 β的表达，以及肺中AM焦亡的百分比，以及血清中HMGB1和BALF的水平。因此，我们的数据表明，Nlrp3/ asc介导的AM焦亡增加了CPB诱导ALI中HMGB1的分泌。这些发现可能为减少CPB期间的肺损伤和炎症反应提供一种治疗策略。
Our previous study showed that high levels of HMGB1 existed in rats following cardiopulmonary bypass (CPB)-induced acute lung injury (ALI) and neutralization of high-mobility group box 1(HMGB1) reduced CPB-induced ALI. However, the mechanism by which CPB increases HMGB1 secretion is unclear. Recent studies have shown that inflammasome-mediated cell pyroptosis promotes HMGB1 secretion. This study aimed to investigate the relationship between inflammasome-mediated pyroptosis and HMGB1 in CPB-related ALI. We employed oxygen-glucose deprivation (OGD)-induced alveolar macrophage (AM) NR8383 pyroptosis to measure HMGB1 secretion. We found that OGD significantly increased the levels of caspase-1 cleaved p10, IL-1 beta and ASC expression, caspase-1 activity and the frequency of pyroptotic AM, and promoted the cytoplasm transportation and secretion of HMGB1, which were significantly mitigated by ASC silencing or pretreatment with glyburide (a Nlrp3 inhibitor) in AM. CPB also increased the expression levels of Nlrp3, ASC, caspase-1 P10, and IL-1 beta, and the percentages of AM pyroptosis in the lungs of experimental rats accompanied by increased levels of serum and bronchoalveolar lavage fluid (BALF) HMGB1. Treatment with glyburide significantly mitigated the CPB-increased ASC, caspase-1 p10 and IL-1 beta expression, and the percentages of AM pyroptosis in the lungs, as well as the levels of HMGB1 in serum and BALF in rats. Therefore, our data indicated that the Nlrp3/ASC-mediated AM pyroptosis increased HMGB1 secretion in ALI induced by CPB. These findings may provide a therapeutic strategy to reduce lung injury and inflammatory responses during CPB.