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Published on: July 6, 2019
Nuclear factor-kappaB decoy oligodeoxynucleotides prevent acute lung injury in mice with cecal ligation and
Naoyuki Matsuda1, Yuichi Hattori, Subrina Jesmin
1Department of Pharmacology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Abstract:
The transcription factor nuclear factor-kappaB (NF-kappaB) plays a key role in expression of many inflammatory genes responsible for the pathophysiology of sepsis-induced acute lung injury. We investigated whether the introduction of synthetic double-stranded oligodeoxynucleotides (ODNs) with consensus NF-kappaB sequence as transcription factor decoy can prevent acute lung injury with suppression of pulmonary expression of multiple genes involved in its pathological process in a cecal ligation and puncture septic mouse model. NF-kappaB decoy ODNs were introduced with the aid of the hemagglutinating virus of Japan-envelope vector method. Northern blot analysis indicated that transfection of NF-kappaB decoy ODN, but not of its scrambled form, resulted in a significant inhibition of sepsis-induced gene overexpression of inducible nitric-oxide synthase (iNOS), cyclooxygenase-2, histamine H(1)-receptor, platelet-activating factor receptor, and bradykinin B(1) and B(2) receptors in lung Histological damage in lungs tissues. (wall thickening, inflammatory infiltrate, and hemorrhage), increased pulmonary vascular permeability, and blood gas exchange impairment were clearly documented in mice after cecal ligation and puncture. These changes were strongly eliminated by the introduction of NF-kappaB decoy but not of scrambled ODN. The effects of the iNOS inhibitor FR260330 on these histological and functional derangements compared unfavorably with those of NF-kappaB decoy ODN transfection. Our results suggest that ODN decoy, acting as in vivo competitor for the transcription factor's ability to bind to cognate recognition sequence, may represent an effective strategy in the treatment of septic acute lung injury.
Insights
Synthetic oligodeoxynucleotides (ODNs) targeting nuclear factor-kappaB (NF-kappaB) effectively prevented sepsis-induced acute lung injury in mice. This approach suppressed key inflammatory gene expression and improved lung function, offering a potential therapeutic strategy.
Area of Science:
- Molecular Biology
- Immunology
- Pathophysiology
Background:
- Sepsis-induced acute lung injury (ALI) involves the transcription factor nuclear factor-kappaB (NF-kappaB) and inflammatory gene expression.
- Current treatments for sepsis-induced ALI have limitations.
Purpose of the Study:
- To investigate the efficacy of NF-kappaB decoy oligodeoxynucleotides (ODNs) in preventing sepsis-induced ALI.
- To assess the impact of NF-kappaB decoy ODNs on pulmonary gene expression and lung injury markers.
Main Methods:
- A cecal ligation and puncture (CLP) septic mouse model was used.
- NF-kappaB decoy ODNs were delivered using the hemagglutinating virus of Japan-envelope vector.
- Gene expression was analyzed by Northern blot; lung histology, vascular permeability, and blood gas exchange were evaluated.
Main Results:
- NF-kappaB decoy ODNs significantly inhibited sepsis-induced overexpression of iNOS, COX-2, and other inflammatory receptors in the lungs.
- Decoy ODNs ameliorated histological lung damage, reduced vascular permeability, and improved blood gas exchange.
- The therapeutic effect of NF-kappaB decoy ODNs surpassed that of the iNOS inhibitor FR260330.
Conclusions:
- NF-kappaB decoy ODNs act as in vivo competitors for NF-kappaB binding, effectively suppressing gene expression.
- This strategy shows promise as a novel treatment for sepsis-induced acute lung injury.
