Department of Critical Care Medicine, Union Hospital, Tongji Medical College, HuazhongUniversity of Science and Technology, Wuhan, Hubei 430022, China; Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College,Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Department of Anesthesiology, Clinical Medical School of Yangzhou University (Subei People's Hospital of Jiangsu Province), Yangzhou, Jiangsu Province, PR China.
Department of Anesthesiology, Clinical Medical School of Yangzhou University (Subei People's Hospital of Jiangsu Province), Yangzhou, Jiangsu Province, PR China.
Int Immunopharmacol. 2020 Apr;81:106257. doi: 10.1016/j.intimp.2020.106257. Epub 2020 Feb 7.
The activation of NLRP3 inflammasome and NF-κB pathway, associating with oxidativestress, have been implicated in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). NecroX-5 has been reported to exhibit theeffectsofanti-oxidation and anti-stress in various diseases. However, the role of NecroX-5 in ALI has not been explicitly demonstrated. The aim of this study was to explore the therapeutic effects and potential mechanism action of NecroX-5 on ALI. Here, we found that NecroX-5 pretreatment dramatically diminished the levels of IL-1β, IL-18 and ROS in in RAW264.7 cells challenged with LPS and ATP. Furthermore, NecroX-5 suppressed the activation of NLRP3 inflammasome and NF-κB signalpathway. In addition, NecroX-5 also inhibited the thioredoxin-interacting protein (TXNIP) expression. In vivo, NecroX-5 reduced the LPS-induced lung histopathological injury, the number of TUNEL-positive cells, lung wet/dry (W/D) ratio, levels of total protein and inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) in mice. Additionally, LPS-induced upregulation of myeloperoxidase (MPO), ROS production and malondialdehyde (MDA) were inhibited by NecroX-5 administration. Thus, our results demonstrate that NecroX-5 protects against LPS-induced ALI by inhibiting TXNIP/NLRP3 and NF-κB.
NLRP3 炎性小体和 NF-κB 通路的激活与氧化应激有关，已被认为与急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的发展有关。NecroX-5 已被报道在各种疾病中具有抗氧化和抗应激作用。然而，NecroX-5 在 ALI 中的作用尚未明确证实。本研究旨在探讨 NecroX-5 对 ALI 的治疗作用及潜在的作用机制。在这里，我们发现 NecroX-5 预处理可显著降低 LPS 和 ATP 刺激的 RAW264.7 细胞中 IL-1β、IL-18 和 ROS 的水平。此外，NecroX-5 抑制 NLRP3 炎性小体和 NF-κB 信号通路的激活。此外，NecroX-5 还抑制硫氧还蛋白相互作用蛋白（TXNIP）的表达。在体内，NecroX-5 减轻了 LPS 诱导的肺组织病理损伤，减少了 TUNEL 阳性细胞的数量，降低了肺湿/干（W/D）比，降低了支气管肺泡灌洗液（BALF）中的总蛋白和炎症细胞因子水平。此外，NecroX-5 还抑制了 LPS 诱导的髓过氧化物酶（MPO）、ROS 产生和丙二醛（MDA）的上调。因此，我们的研究结果表明，NecroX-5 通过抑制 TXNIP/NLRP3 和 NF-κB 来保护 LPS 诱导的 ALI。
