Intratracheally instilled mannosylated cationic liposome/NFκB decoy complexes for effective prevention of LPS-induced lung inflammation.
The nuclear factor kappa B (NFκB) signaling pathway is a key mechanism in the pathophysiology of lung inflammation. NFκB is critically responsible for the expression of pro-inflammatory mediators following activation. The specific inhibition of NFκB by a NFκB decoy via inhalation appears to improve therapeutic effects. However, administration of naked NFκB decoy limits the efficacy of the decoy strategy due to low targeting ability to immune cells such as alveolar macrophages. In this study, we have assessed the effect of alveolar macrophage-targeted NFκB decoy by mannosylated (Man) cationic liposomes in a LPS-induced lung inflammation model after intratracheal administration. The complex of Man-cationic liposome/NFκB decoy was physically stable during spraying. Man-cationic liposome/NFκB decoy complex was selectively delivered to alveolar macrophages for subsequent localization of NFκB decoy in the cytoplasm and to a lesser extent in the nucleus. In the LPS-induced lung inflammation model, pre-treatment with Man-cationic liposome/50μg NFκB decoy complex significantly inhibited the release of TNF-α, IL-1β and CINC-1, neutrophil infiltration and NFκB activation compared with naked NFκB decoy, cationic liposome/NFκB decoy complex and Man-cationic liposome/scrambled decoy complex treatments. This study demonstrates the sufficient targeting of NFκB decoy using Man-cationic liposomes in a novel effective anti-inflammatory therapy for lung inflammation.
Wijagkanalan
Wassana
W
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Kawakami
Shigeru
S
Higuchi
Yuriko
Y
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002412:Cations; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008081:Liposomes; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008358:Mannose / Q000737:chemistry*; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000893:Anti-Inflammatory Agents; D002412:Cations; D016207:Cytokines; D008070:Lipopolysaccharides; D008081:Liposomes; D016328:NF-kappa B; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D009195:Peroxidase; D008358:Mannose