title: Niacin and Selenium Attenuate Sepsis-Induced Lung Injury by Up-Regulating Nuclear Factor Erythroid 2-Related Factor 2 Signaling.
abstract: To determine whether the combination therapy of niacin and selenium attenuates lung injury and improves survival during sepsis in rats and whether its benefits are associated with the activation of the glutathione redox cycle and up-regulation of nuclear factor erythroid 2-related factor 2.
  
  
  
  Prospective laboratory study.
  
  
  
  University laboratory.
  
  
  
  Human lung microvascular endothelial cells and male Sprague-Dawley rats (n = 291).
  
  
  
  In lipopolysaccharide-exposed cells, the dose-related effects of niacin and selenium were assessed, and the therapeutic effects of the combination therapy of niacin (0.9 mM) and selenium (1.5 μM) were evaluated. The role of nuclear factor erythroid 2-related factor 2 was determined using nuclear factor erythroid 2-related factor 2 knockdown cells. In endotoxemic and cecal ligation and puncture with antibiotics rats, the therapeutic effects of the posttreatments of clinically relevant doses of niacin (360 mg/kg) and selenium (60 μg/kg) were evaluated.
  
  
  
  Combination therapy reduced the hydrogen peroxide level via the synergistic activation of the glutathione redox cycle, which involves niacin-induced increases in glutathione reductase activity, and reduced the glutathione level and a selenium-induced increase in glutathione peroxidase activity. Combination therapy contributed to the up-regulation of nuclear factor erythroid 2-related factor 2, enhancement of glutathione synthesis, and down-regulation of nuclear factor κB signaling, but nuclear factor erythroid 2-related factor 2 knockdown inhibited the enhancement of glutathione synthesis and down-regulation of the nuclear factor κB pathway. The therapeutic effects of combination therapy on endotoxemic rats were consistent with those on lipopolysaccharide-exposed cells. In addition, the posttreatment of combination therapy attenuated lung injury and improved survival in endotoxemic and cecal ligation and puncture with antibiotics rats. However, individual therapies of niacin or selenium failed to achieve these benefits.
  
  
  
  The combination therapy of niacin and selenium attenuated lung injury and improved survival during sepsis. Its therapeutic benefits were associated with the synergistic activation of the glutathione redox cycle, reduction of hydrogen peroxide level, and up-regulation of nuclear factor erythroid 2-related factor 2.
authors.affiliation: 1Department of Emergency Medicine, Seoul National University Hospital, Seoul, Korea. 2Department of Emergency Medicine, National Medical Center, Seoul, Korea.
authors.forename: Woon Yong
authors.initials: WY
authors.lastname: Kwon
authors.forename: Gil Joon
authors.initials: GJ
authors.lastname: Suh
authors.forename: Kyung Su
authors.initials: KS
authors.lastname: Kim
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Jung
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Jae Seong
authors.initials: JS
authors.lastname: Kim
authors.forename: Kyoung Min
authors.initials: KM
authors.lastname: You
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D042783:Endothelial Cells; D019446:Endotoxemia / Q000150:complications / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury / Q000188:drug therapy* / Q000378:metabolism* / Q000382:microbiology; D008297:Male; D009249:NADP / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009525:Niacin / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012643:Selenium / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000975:Antioxidants; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C082161:lipopolysaccharide A; D009525:Niacin; D009249:NADP; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione; D012643:Selenium; D019803:Glutathione Disulfide