PDF(Pubmed)
Abstract：
Nuclear factor e2-related factor 2 (Nrf2) plays a key role in cellular resistance to oxidative stress injury. Oxidative stress injury, caused by Nrf2 imbalance, results in increased pyroptosis, DNA damage, and inflammatory activation, which may lead to the arrest of alveolar development and bronchopulmonary dysplasia (BPD) in premature infants under hyperoxic conditions. We established a BPD mouse model to investigate the effects of tert-butylhydroquinone (TBHQ), an Nrf2 activator, on oxidative stress injury, pyroptosis, NLRP3 inflammasome activation, and alveolar development. TBHQ reduced abnormal cell death in the lung tissue of BPD mice and restored the number and normal structure of the alveoli. TBHQ administration activated the Nrf2/heme oxygenase-1 (HO-1) signaling pathway, resulting in the decrease in the following: reactive oxygen species (ROS), activation of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, and IL-18 and IL-1β expression and activation, as well as inhibition of pyroptosis. In contrast, after Nrf2 gene knockout in BPD mice, there was more severe oxidative stress injury and cell death in the lungs, there were TUNEL + and NLRP3 + co-positive cells in the alveoli, the pyroptosis was significantly increased, and the development of alveoli was significantly blocked. We demonstrated that TBHQ may promote alveolar development by enhancing Nrf2-induced antioxidation in the lung tissue of BPD mice and that the decrease in the NLRP3 inflammasome and pyroptosis caused by Nrf2 activation may be the underlying mechanism. These results suggest that TBHQ is a promising treatment for lung injury in premature infants with hyperoxia.
摘要：
核因子e2相关因子2（Nrf2）在细胞抵抗氧化应激损伤中起关键作用。氧化应激损伤，由Nrf2失衡引起，导致焦亡增加，DNA损伤,和炎症激活，这可能导致高氧条件下早产儿肺泡发育和支气管肺发育不良（BPD）的停止。我们建立了BPD小鼠模型来研究叔丁基对苯二酚（TBHQ）的作用，Nrf2激活剂，对氧化应激损伤，焦亡,NLRP3炎性体激活，和肺泡发育。TBHQ减少了BPD小鼠肺组织中的异常细胞死亡，恢复了肺泡的数量和正常结构。TBHQ给药激活了Nrf2/血红素加氧酶-1（HO-1）信号通路，导致以下物质的减少：活性氧(ROS)，含3（NLRP3）炎性体的NOD样受体pyrin结构域的激活，以及IL-18和IL-1β的表达和激活，以及抑制焦亡。相比之下,在BPD小鼠中Nrf2基因敲除后，肺部有更严重的氧化应激损伤和细胞死亡，肺泡中有TUNEL+和NLRP3+共阳性细胞，焦亡显著增加，肺泡的发育明显受阻。我们证明，TBHQ可能通过增强Nrf2诱导的BPD小鼠肺组织中的抗氧化作用来促进肺泡发育，而Nrf2激活引起的NLRP3炎性体和焦亡的减少可能是潜在的机制。这些结果表明，TBHQ是治疗早产儿高氧肺损伤的有希望的治疗方法。
