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A Decoy Oligonucleotide to NF-κB Delivered through Inhalable Particles Prevents LPS-Induced Rat Airway Inflammation
- Source :
- American Journal of Respiratory Cell and Molecular Biology. 49:288-295
- Publication Year :
- 2013
- Publisher :
- American Thoracic Society, 2013.
-
Abstract
- The inflammatory process plays a crucial role in the onset and progression of several lung pathologies, including cystic fibrosis (CF),andthe involvement of NF-κBis widely recognized.Thespecific inhibition of NF-κB by decoy oligonucleotides delivered within the lung may be beneficial, although rationally designed systems are needed to optimize their pharmacological response. Prompted by this need, we have developed and tested in vivo an inhalable dry powder for the prolonged delivery of a decoy oligodeoxynucleotide to NF-κB (dec-ODN), consisting of large porous particles (LPPs) based on poly(lactic-co-glycolic) acid. First, LPPs containing dec- ODN (dec-ODN LPPs) were engineered to meet the aerodynamic criteria crucial for pulmonary delivery, to gain an effective loading of dec-ODN, to sustain its release, and to preserve its structural integrity in lung lining fluids. We then investigated the effects of dec- ODN LPPs in a rat model of lung inflammation induced by the intratracheal aerosolization of LPS from Pseudomonas aeruginosa. Theresults show that a single intratracheal insufflation of dec-ODN LPPs reduced the bronchoalveolar neutrophil infiltration induced by LPS for up to 72 hours, whereas naked dec-ODN was able to inhibit it only at 6 hours. The persistent inhibition of neutrophil infiltrate was associated with reduced NF-κB/DNA binding activity, as well as reduced IL-6, IL-8, and mucin-2 mRNA expression in lung homogenates. We consider it noteworthy that the developed LPPs, preventing the accumulation of neutrophils and NF-κB-related gene expression, may provide a new therapeutic option for the local treatment of inflammation associated with lung disease. Copyright © 2013 by the American Thoracic Society.
- Subjects :
- Lipopolysaccharides
Male
Pulmonary and Respiratory Medicine
government.form_of_government
Clinical Biochemistry
Cystic fibrosis
chemistry.chemical_compound
Polylactic Acid-Polyglycolic Acid Copolymer
Rat lung inflammation
medicine
Animals
Lactic Acid
Pseudomonas aeruginosa-LPS
Interleukin 8
Rats, Wistar
Pulmonary delivery
PLGA dry powder
Interleukin 6
Molecular Biology
Antisense therapy
Lung
biology
Interleukin-6
business.industry
NF-kappa B
NF-κB
Pneumonia
Cell Biology
respiratory system
medicine.disease
NFKB1
Rats
Disease Models, Animal
medicine.anatomical_structure
Gene Expression Regulation
Neutrophil Infiltration
Oligodeoxyribonucleotides
chemistry
NF-κB oligonucleotide decoy
Pseudomonas aeruginosa
Immunology
biology.protein
government
Decoy
business
Polyglycolic Acid
Subjects
Details
- ISSN :
- 15354989 and 10441549
- Volume :
- 49
- Database :
- OpenAIRE
- Journal :
- American Journal of Respiratory Cell and Molecular Biology
- Accession number :
- edsair.doi.dedup.....33a57bcff991d71cc99241a6e4ce1682