Oridonin attenuates carrageenan-induced pleurisy via activation of the KEAP-1/Nrf2 pathway and inhibition of the TXNIP/NLRP3 and NF-κB pathway in mice
Oridonin attenuates carrageenan-induced pleurisy via activation of the KEAP-1/Nrf2 pathway and inhibition of the TXNIP/NLRP3 and NF-κB pathway in mice
复制标题
DOI：
10.1007/s10787-019-00644-y
复制
发表时间：
2019-09
影响因子：
5.8
通讯作者：
Huahong Yang;Jingbo Huang;Yanli Gao;Zhongmei Wen;Liping Peng;X. Ci
中科院分区：
文献类型：
--
作者：
Huahong Yang;Jingbo Huang;Yanli Gao;Zhongmei Wen;Liping Peng;X. Ci
经典的NLRP 3炎性体和NF-κB分子通路在许多炎症相关疾病中被激活，例如胸膜炎。由于冬凌草甲素（Ori）已被指示为具有强抗炎体活性的共价NLRP 3抑制剂，因此我们在此旨在评估Ori在角叉菜胶（CAR）诱导的胸膜炎的小鼠模型中的作用。结果表明，CAR引起肺组织肿胀和渗出以及炎性因子（TNF-α、IL-6和IL-1β）的释放，这些作用被Ori治疗显著降低。此外，CAR组的渗出液中发现中性粒细胞浸润、蛋白质浓度和体积增加，这些现象被Ori治疗抑制。在细胞通路方面，Ori可以减轻CAR激活的NF-κB和TXNIP/NLRP 3通路。此外，氧化应激被证明参与胸膜炎的发病机制，但可能的机制仍有待探讨。在此，Ori逆转了CAR诱导的GSH和SOD的消耗以及CAR诱导的ROS、MPO和MDA水平的增加。此外，Ori抑制NOX-4水平，启动KEAP-1与Nrf 2的解离，激活下游基因HO-1，并对CAR诱导的胸膜炎发挥抗氧化作用。总之，Ori通过Nrf 2依赖性抗氧化和NLRP 3依赖性抗炎特性提供针对CAR诱导的胸膜炎的保护。
The classic NLRP3 inflammasome and NF-κB molecular pathways are activated in many inflammatory-related diseases, such as pleurisy. Because oridonin (Ori) has been indicated as a covalent NLRP3 inhibitor with strong anti-inflammasome activity, we herein aimed to assess the effects of Ori in a mouse model of carrageenan (CAR)-induced pleurisy. The results showed that CAR caused hemorrhaging and exudation of lung tissues and the release of inflammatory factors (TNF-α, IL-6 and IL-1β), effects that were significantly reduced by treatment with Ori. In addition, increased neutrophil infiltration, protein concentrations and volumes were found in the exudates of the CAR group, and these phenomena were suppressed by Ori treatment. Regarding cellular pathways, Ori could alleviate the CAR-activated NF-κB and TXNIP/NLRP3 pathways. Additionally, oxidative stress was shown to be involved in the pathogenesis of pleurisy, but possible mechanisms remain to be explored. Herein, Ori reversed the CAR-induced depletion of GSH and SOD and the CAR-induced increases in ROS, MPO and MDA levels. Furthermore, Ori inhibited NOX-4 levels, initiated the dissociation of KEAP-1 from Nrf2, activated the downstream genes HO-1 and exerted antioxidative effects on CAR-induced pleurisy. In conclusion, Ori conferred protection against CAR-induced pleurisy via Nrf2-dependent antioxidative and NLRP3-dependent anti-inflammatory properties.