Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Biochem Biophys Res Commun. 2018 Sep 18;503(4):3031-3037. doi: 10.1016/j.bbrc.2018.08.089. Epub 2018 Aug 23.
Lung ischemia-reperfusion (IR) occurs in many circumstances and leads to impaired lung function. The NACHT, LRR and PYD domains-containing protein 3 (Nlrp3) inflammasome is reportedly activated during lung IR. Mcc950 is a recently developed Nlrp3 inhibitor. The aim of our study was to test the efficacy of Mcc950 on lung IR injury and to investigate the role of reactive oxygen species (ROS) in Nlrp3 inflammasome activation using a murine lung IR model. The results of the current study confirmed that Nlrp3 was upregulated and activated during lung IR, and inhibiting oxidative stress by the ROS scavenger edaravone attenuated Nlrp3 inflammasome activation. Mcc950 pretreatment significantly alleviated IR-induced lung injury by reducing production of the proinflammatory cytokines Il-1β and Il-18 and inhibiting neutrophil infiltration and cell apoptosis. Protein coimmunoprecipitation revealed that Mcc950 partially blocked the interaction between Nlrp3 and Nek7 (NimA-related protein kinase 7). Therefore, we conclude that ROS-dependent activation of the Nlrp3 inflammasome contributed to lung IR injury. Mcc950 significantly reduced lung IR injury by blocking Nlrp3 inflammasome activation, and the mechanism was partially attributed to inhibition of the interaction between Nlrp3 and Nek7. Thus, Mcc950 is a promising treatment for the prevention of lung IR injury.
肺缺血再灌注（IR）发生在许多情况下，导致肺功能受损。据报道，NACHT、LRR 和 PYD 结构域包含蛋白 3（Nlrp3）炎症小体在肺 IR 期间被激活。Mcc950 是一种新开发的 Nlrp3 抑制剂。我们的研究旨在测试 Mcc950 对肺 IR 损伤的疗效，并使用鼠肺 IR 模型研究活性氧（ROS）在 Nlrp3 炎症小体激活中的作用。本研究结果证实，Nlrp3 在肺 IR 期间上调和激活，ROS 清除剂依达拉奉抑制氧化应激可减弱 Nlrp3 炎症小体激活。Mcc950 预处理通过减少促炎细胞因子 Il-1β 和 Il-18 的产生以及抑制中性粒细胞浸润和细胞凋亡，显著减轻 IR 诱导的肺损伤。蛋白质免疫共沉淀显示，Mcc950 部分阻断了 Nlrp3 和 Nek7（NimA 相关蛋白激酶 7）之间的相互作用。因此，我们得出结论，ROS 依赖性 Nlrp3 炎症小体激活导致肺 IR 损伤。Mcc950 通过阻断 Nlrp3 炎症小体激活显著减轻肺 IR 损伤，其机制部分归因于抑制 Nlrp3 和 Nek7 之间的相互作用。因此，Mcc950 是预防肺 IR 损伤的一种有前途的治疗方法。
