上睑下垂
药理学
免疫印迹
炎症体
腹腔注射
脂多糖
医学
体内
TLR4型
化学
免疫学
炎症
生物化学
生物
基因
生物技术
作者
Huayu Li,Mengyan Li,Chao Dong,Bing Liu
出处
期刊:Toxicology Research
[Oxford University Press]
日期:2022-05-14
卷期号:11 (3): 437-450
被引量:4
标识
DOI:10.1093/toxres/tfac020
摘要
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. It is of great interest to us that dimethyl fumarate (DMF) has been shown to have anti-inflammatory effects. The aim of this study was to investigate whether DMF could alleviate lipopolysaccharide(LPS)-induced ALI, and to explore its mechanism of action.We established a mice model of ALI with intratracheal instillation of LPS and intraperitoneal injection of DMF to treat ALI. The pathological damage and inflammatory response of lung tissues were observed by hematoxylin and eosin (H&E) staining, ELISA assay and western blot. ATP plus LPS was used for the establishment of ALI in vitro model, the therapeutic effects of DMF was explored by ELISA assay, RT-qPCR, western blot, and flow cytometry, and the therapeutic mechanisms of DMF was explored by administration of Brusatol (BT), a nuclear factor erythroid-2-related factor 2 (Nrf2) inhibitor.We found that intraperitoneal injection of DMF significantly reduced LPS-induced the pulmonary injury, pulmonary edema, and infiltration of inflammatory mediators. In LPS-induced ALI, NLRP3 inflammasome-mediated pyroptosis was markedly activated, followed by cleavage of caspase-1 and GSDMD. DMF inhibited the activation of the NLRP3 inflammasome and pyroptosis in both lung of ALI mice and ATP plus LPS-induced BEAS-2B cells. Mechanistically, DMF enhanced expressions of Nrf2, leading to inactivation of NLRP3 inflammasome and reduced pyroptosis in vivo and in vitro. Conversely, BT reduced the inhibitory effects of DMF on NLRP3 inflammasome and pyroptosis, and consequently blocked the improvement roles of DMF on ALI.DMF could improve LPS-induced ALI via inhibiting NLRP3 inflammasome and pyroptosis, and that these effects were mediated by triggering Nrf2 expression, suggesting a therapeutic potential of DMF as an anti-inflammatory agent for ALI/ARDS treatment.
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