title: Eukaryotic translation initiation factor 5A small interference RNA-liposome complexes reduce inflammation and increase survival in murine models of severe sepsis and acute lung injury.
abstract: BACKGROUND
  Many novel therapeutics have failed to reduce all-cause mortality associated with severe sepsis. Eukaryotic translation initiation factor 5A (eIF5A) is a regulator of apoptosis as well as inflammatory cell activation, making it a potential target for sepsis therapy.
  
  
  METHODS
  In a murine model of severe sepsis, mice were intraperitoneally challenged with lipopolysaccharide (LPS). Mice were treated both before and after LPS challenge with liposome complexes containing either an eIF5A-specific or control small interference RNA (siRNA), and both survival and serum concentrations of inflammatory cytokines were monitored. The ability of eIF5A siRNA to reduce inflammatory cytokines was also tested in a model of acute lung injury established by intranasal administration of LPS to mice.
  
  
  RESULTS
  There was a statistically significant increase in the rate of survival for mice intraperitoneally challenged with LPS that received eIF5A siRNA, compared with that noted for mice that received control siRNA (71% vs. 5%; P< .001), as well as a reduction in cytokine expression in serum. Concentrations of proinflammatory cytokines were also reduced in the lung homogenates and serum of mice that were intranasally challenged with LPS and received eIF5A siRNA (P< or = .05).
  
  
  CONCLUSIONS
  eIF5A siRNA-liposome complexes reduced inflammation and contributed to increased survival in a model of severe sepsis, decreased inflammation in a model of acute lung injury, and should be considered for clinical use.
authors.affiliation: Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA. ccm5u@virginia.edu
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Moore
authors.forename: Edward N
authors.initials: EN
authors.lastname: Martin
authors.forename: Grace
authors.initials: G
authors.lastname: Lee
authors.forename: Catherine
authors.initials: C
authors.lastname: Taylor
authors.forename: Richard
authors.initials: R
authors.lastname: Dondero
authors.forename: Leonid L
authors.initials: LL
authors.lastname: Reznikov
authors.forename: Charles
authors.initials: C
authors.lastname: Dinarello
authors.forename: John
authors.initials: J
authors.lastname: Thompson
authors.forename: W Michael
authors.initials: WM
authors.lastname: Scheld
mesh_terms: D000208:Acute Disease; D000818:Animals; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000628:therapy*; D008070:Lipopolysaccharides / Q000633:toxicity; D008081:Liposomes / Q000737:chemistry / Q000494:pharmacology*; D008171:Lung Diseases / Q000139:chemically induced / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D008070:Lipopolysaccharides; D008081:Liposomes; D010448:Peptide Initiation Factors; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A
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