Pharmacologic Suppression of Inflammation by a Diphenyldifluoroketone, EF24, in a Rat Model of Fixed-Volume Hemorrhage Improves Survival

• Published in: The Journal of pharmacology and experimental therapeutics 2013-11, Vol.347 (2), p.346-356
• Main Authors: Yadav, Vivek R., Sahoo, Kaustuv, Roberts, Pamela R., Awasthi, Vibhudutta
• Format: Article
• Language: English
• Subjects: 3,5-bis(2-fluorobenzylidene)piperidin-4-one; 8-oxoguanine DNA glycosylase 1; Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; APE1; apurinic endonuclease; Benzylidene Compounds - administration & dosage; Benzylidene Compounds - pharmacology; Benzylidene Compounds - therapeutic use; COX-2; Cyclooxygenase 2 - biosynthesis; cyclooxygenase-2; Cytokines - blood; Cytokines - immunology; damage-associated molecular pattern; DAMP; Disease Models, Animal; Drug Discovery and Translational Medicine; EF24; ELISA; enzyme-linked immunosorbent assay; ethyl pyruvate; HEM; Heme Oxygenase (Decyclizing) - biosynthesis; heme oxygenase–1; hemorrhage; hemorrhagic shock; hexadecyltrimethylammonium bromide; high-mobility group box 1; HMGB1; HO-1; horseradish peroxidase; HRP; HTAB; Hypovolemia - etiology; Hypovolemia - immunology; Hypovolemia - pathology; Hypovolemia - prevention & control; I/R; IFN-γ; inducible nitric-oxide synthase; iNOS; interferon-γ; interleukin; ischemia/reperfusion; Lung - drug effects; Lung - immunology; Lung - pathology; macrophage inflammatory protein; Male; MCP-1; mean arterial blood pressure; MIP; monocyte chemotactic protein–1; NF-κB; Nitric Oxide Synthase Type II - biosynthesis; nuclear factor-κB; OGG1; pattern recognition receptor; Piperidones - administration & dosage; Piperidones - pharmacology; Piperidones - therapeutic use; PRR; RANTES; Rats; Rats, Sprague-Dawley; regulated and normal T-cell expressed and secreted; Shock, Hemorrhagic - complications; Shock, Hemorrhagic - drug therapy; Shock, Hemorrhagic - immunology; Shock, Hemorrhagic - pathology; SOD1; superoxide dismutase 1; Survival Analysis; TLR4; TNF; Toll-like receptor 4; Transcription Factor RelA - antagonists & inhibitors; Transcription Factor RelA - biosynthesis; tumor necrosis factor
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.113.208009

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.