title: Pharmacologic suppression of inflammation by a diphenyldifluoroketone, EF24, in a rat model of fixed-volume hemorrhage improves survival.
abstract: 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.
authors.affiliation: 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.
authors.forename: Vivek R
authors.initials: VR
authors.lastname: Yadav
authors.forename: Kaustuv
authors.initials: K
authors.lastname: Sahoo
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Roberts
authors.forename: Vibhudutta
authors.initials: V
authors.lastname: Awasthi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001597:Benzylidene Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D020896:Hypovolemia / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010881:Piperidones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; D000893:Anti-Inflammatory Agents; D001597:Benzylidene Compounds; D016207:Cytokines; D010881:Piperidones; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D051546:Cyclooxygenase 2