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...

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Bibliographic Details
Published in:The Journal of infectious diseases 2008-11, Vol.198 (9), p.1407-1414
Main Authors: Moore, Christopher C., Martin, Edward N., Lee, Grace, Taylor, Catherine, Dondero, Richard, Reznikov, Leonid L., Dinarello, Charles, Thompson, John, Scheld, W. Michael
Format: Article
Language:English
Subjects:
Acute Disease
Animals
Apoptosis
Bacterial diseases
Bacterial sepsis
Biological and medical sciences
Cell lines
Cytokines
Eukaryotic Translation Initiation Factor 5A
Female
Fundamental and applied biological sciences. Psychology
Human bacterial diseases
Infectious diseases
Inflammation
Inflammation - chemically induced
Inflammation - therapy
Lipopolysaccharides - toxicity
Liposomes - chemistry
Liposomes - pharmacology
Lung Diseases - chemically induced
Lung Diseases - therapy
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Microbiology
Pathogenesis and Host Response
Peptide initiation factors
Peptide Initiation Factors - genetics
Peptide Initiation Factors - metabolism
Polyamines
RNA Interference
RNA, Small Interfering - chemistry
RNA, Small Interfering - pharmacology
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Sepsis
Small interfering RNA
T lymphocytes
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Summary: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 eIF5Aspecific 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 â©˝ .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.
ISSN:0022-1899
1537-6613
DOI:10.1086/592222