Department of Pharmaceutical Sciences (V.R.Y., K.S., V.A.) and Department of Anesthesiology (P.R.R.), University of Oklahoma Health Science Center, Oklahoma City, Oklahoma.
J Pharmacol Exp Ther. 2013 Nov;347(2):346-56. doi: 10.1124/jpet.113.208009. Epub 2013 Aug 30.
An exaggerated release of proinflammatory cytokines and accompanying inflammation contributes to the development of multiple organ failure after hemorrhagic shock. Here, we tested the nuclear factor (NF) κ-light-chain-enhancer of activated B cell (NF-κB)-mediated transcriptional control of inflammatory pathways as a target in the management of hemorrhage-induced inflammation. We performed a study in a rat model of fixed-volume hemorrhage to investigate the anti-inflammatory effects of the diphenyldifluoroketone EF24 [3,5-bis(2-fluorobenzylidene)piperidin-4-one], an NF-κB inhibitor, in lung tissue. EF24 treatment (0.4 mg/kg) significantly prevented the upregulation of inflammatory biomarkers in rats subjected to 50% hemorrhage and preserved the pulmonary histology in hemorrhaged rats. The lung tissue from treated rats showed marked suppression of the hemorrhage-mediated induction of Toll-like receptor 4, phospho-p65 NF-κB, inducible nitric-oxide synthase, heme oxygenase-1, and cyclooxygenase-2 (COX-2). The hemorrhage-induced COX-2 activity was also significantly inhibited by the EF24 treatment. At the same time, EF24 induced nuclear factor (erythroid-derived 2)-like 2-mediated protective mechanisms against oxidative stress. EF24 also reduced hemorrhage-induced lung myeloperoxidase activity. The plasma levels of proinflammatory tumor necrosis factor-α, interleukin (IL)-6, IL-1α, and IL-1β were lower in EF24-treated rats than in untreated rats. Moreover, there was a significant reduction in the pulmonary expression of high-mobility group B1 protein. These biochemical effects were accompanied by a significant improvement in the survival of rats administered with EF24 as compared with the rats receiving vehicle control (P < 0.05). Overall, the results suggest that EF24 attenuates hemorrhage-induced inflammation and could serve as a salutary anti-inflammatory agent in resuscitation strategies.
促炎细胞因子的过度释放和伴随的炎症导致失血性休克后多器官衰竭的发展。在这里，我们测试了核因子 (NF)-κB 激活 B 细胞的轻链增强子 (NF-κB) 介导的炎症途径的转录控制作为管理出血引起的炎症的靶点。我们在固定容量出血的大鼠模型中进行了一项研究，以研究二苯二氟代酮 EF24[3,5-双(2-氟苄叉基)哌啶-4-酮]，一种 NF-κB 抑制剂，对肺组织中炎症的抗炎作用。EF24 治疗（0.4mg/kg）显著阻止了 50%出血大鼠中炎症生物标志物的上调，并在出血大鼠中保存了肺组织学。用治疗大鼠的肺组织显示出对 TLR4、磷酸化 p65 NF-κB、诱导型一氧化氮合酶、血红素加氧酶-1 和环氧化酶-2 (COX-2) 的出血介导诱导的明显抑制。EF24 治疗也显著抑制了 COX-2 的活性。同时，EF24 诱导了核因子 (红系衍生 2)-样 2 介导的抗氧化应激保护机制。EF24 还降低了出血引起的肺髓过氧化物酶活性。与未治疗大鼠相比，EF24 治疗大鼠的血浆中促炎肿瘤坏死因子-α、白细胞介素 (IL)-6、IL-1α 和 IL-1β 水平较低。此外，EF24 治疗还显著降低了肺组织高迁移率族蛋白 B1 蛋白的表达。这些生化作用伴随着接受 EF24 治疗的大鼠与接受载体对照的大鼠相比，生存率显著提高（P<0.05）。总体而言，结果表明 EF24 减轻了出血引起的炎症，并可作为复苏策略中的有益抗炎剂。
