Department of Anesthesiology, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Ninth People's Hospital, No. 639 Zhizaoju Road, Shanghai 200011, China.
Department of Anesthesiology, Shanghai JiaoTong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Ninth People's Hospital, No. 639 Zhizaoju Road, Shanghai 200011, China.
Free Radic Biol Med. 2018 Jun;121:78-85. doi: 10.1016/j.freeradbiomed.2018.04.557. Epub 2018 Apr 17.
Lung injury, which is associated with systemic inflammatory responses, is a common problem with significant morbidity and mortality. Here, we examined the involvement of toll-like receptor 4 (TLR4) and nuclear factor erythroid 2-related factor 2 (Nrf2) on intestinal ischemia-reperfusion (I/R)-induced lung injury in vivo and in vitro. Analysis of lung tissues in Nrf2-knockout mice by western blotting, immunohistochemistry, and TUNEL assay, and analysis of bronchoalveolar lavage fluid showed that Nrf2 deficiency upregulated TLR4, enhanced I/R-induced lung injury, apoptosis, inflammation, and autophagy, and increased the I/R-induced inactivation of Akt. In mouse lung epithelial cells subjected to oxygen and glucose deprivation/reperfusion (OGD/Rep), Nrf2 silencing increased the OGD/Rep-induced upregulation of TLR4 and MyD88 and downregulation of HO-1, and exacerbated OGD/Rep-induced apoptosis, autophagy, and the downregulation of phospho-Akt. TLR4 silencing and Akt inhibition experiments indicated that OGD/Rep-induced cell death by suppressing Akt signaling, and Nrf2 protected lung cells by modulating TLR4 and Akt signaling. These results indicated that the Nrf2/TLR4/Akt axis plays a role in inflammation-associated lung damage, suggesting potential therapeutic targets for the treatment of lung injury.
肺损伤与全身炎症反应有关，是一种常见的疾病，具有显著的发病率和死亡率。在这里，我们研究了 Toll 样受体 4（TLR4）和核因子红细胞 2 相关因子 2（Nrf2）在体内和体外肠缺血再灌注（I/R）诱导的肺损伤中的作用。通过 Western blot、免疫组织化学和 TUNEL 分析对 Nrf2 敲除小鼠的肺组织进行分析，以及对支气管肺泡灌洗液进行分析，结果表明 Nrf2 缺失上调了 TLR4，增强了 I/R 诱导的肺损伤、细胞凋亡、炎症和自噬，并增加了 I/R 诱导的 Akt 失活。在氧葡萄糖剥夺/再灌注（OGD/Rep）处理的小鼠肺上皮细胞中，Nrf2 沉默增加了 OGD/Rep 诱导的 TLR4 和 MyD88 的上调以及 HO-1 的下调，并加剧了 OGD/Rep 诱导的细胞凋亡、自噬和磷酸化 Akt 的下调。TLR4 沉默和 Akt 抑制实验表明，OGD/Rep 通过抑制 Akt 信号诱导细胞死亡，而 Nrf2 通过调节 TLR4 和 Akt 信号来保护肺细胞。这些结果表明，Nrf2/TLR4/Akt 轴在炎症相关的肺损伤中发挥作用，为治疗肺损伤提供了潜在的治疗靶点。
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