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.
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.
Moore
Christopher C
CC
Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA. ccm5u@virginia.edu
Martin
Edward N
EN
Lee
Grace
G
Taylor
Catherine
C
Dondero
Richard
R
Reznikov
Leonid L
LL
Dinarello
Charles
C
Thompson
John
J
Scheld
W Michael
WM
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
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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