title: ETS-GS, a new anti-oxidative drug, protects against lipopolysaccharide-induced acute lung and liver injury.
abstract: BACKGROUND
  Sepsis is a major health threat that remains refractory to treatment. Impairment of normal cellular function due to oxidative stress is implicated in organ injury during systemic inflammatory responses. We investigated whether the new anti-oxidative drug, ETS-GS, could inhibit secretion of cytokines and mono-nitrogen oxides, thus reducing organ damage in a rat model of lipopolysaccharide-induced sepsis.
  
  
  METHODS
  Lipopolysaccharide was administered intravenously to male Wistar rats in order to establish a rat model of systemic inflammation. These rats were challenged with or without intravenous ETS-GS. Mouse macrophage RAW264.7 cells were stimulated with lipopolysaccharide, with or without simultaneous ETS-GS treatment, in order to elucidate the mechanism of action.
  
  
  RESULTS
  Histologic examination revealed that ETS-GS markedly reduced lipopolysaccharide-induced interstitial edema and leukocytic infiltration in lung tissue, and lipopolysaccharide-induced bleeding and leukocytic infiltration in liver tissue harvested 12 h after treatment. Cytokine (interleukin-6 and tumor necrosis factor-α) secretion was strongly induced by lipopolysaccharide; this induction was similarly inhibited by ETS-GS treatment. Likewise, lipopolysaccharide-induced secretion of mono-nitrogen oxides was inhibited by ETS-GS. In the in vitro studies, ETS-GS administration inhibited IκB phosphorylation.
  
  
  CONCLUSIONS
  ETS-GS blocked the lipopolysaccharide-induced inflammatory response and protected against acute lung and liver injury normally associated with endotoxemia in this rat model of systemic inflammation. Further, this protection may be mediated through the inhibition of nuclear factor κ-light-chain-enhancer of activated B cells activation. Our results suggest that ETS-GS is a potential therapeutic agent for sepsis.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Oita, Japan. saku@med.oita-u.ac.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hagiwara
authors.forename: Hironori
authors.initials: H
authors.lastname: Koga
authors.forename: Hideo
authors.initials: H
authors.lastname: Iwasaka
authors.forename: Jyunya
authors.initials: J
authors.lastname: Kusaka
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Uchida
authors.forename: Koji
authors.initials: K
authors.lastname: Goto
authors.forename: Isao
authors.initials: I
authors.lastname: Yokoi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Noguchi
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000975:Antioxidants; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009566:Nitrates; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; C568419:gamma-L-glutamyl-S-(2-(((3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12- trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)carbonyl)-3-oxo-3-((2-sulfoethyl)amino)propyl)-L-cysteinylglycine sodium salt; D051550:I-kappa B Kinase