title: Enhanced anti-inflammation of inhaled dexamethasone palmitate using mannosylated liposomes in an endotoxin-induced lung inflammation model.
abstract: Inhalation of bacterial endotoxin induces pulmonary inflammation by activation of nuclear factor kappaB (NFkappaB), production of cytokines and chemokines, and neutrophil activation. Although glucocorticoids are the drugs of choice, administration of free drugs results in adverse effects as a result of a lack of selectivity for the inflammatory effector cells. Because alveolar macrophages play a key role in the inflammatory response in the lung, selective targeting of glucocorticoids to alveolar macrophages offers efficacious pharmacological intervention with minimal side effects. We have demonstrated previously the selective targeting of mannosylated liposomes to alveolar macrophages via mannose receptor-mediated endocytosis after intratracheal administration. In this study, the anti-inflammatory effects of dexamethasone palmitate incorporated in mannosylated liposomes (DPML) at 0.5 mg/kg via intratracheal administration were investigated in lipopolysaccharide-induced lung inflammation in rats. DPML significantly inhibited tumor necrosis factor alpha, interleukin-1beta, and cytokine-induced neutrophil chemoattractant-1 levels, suppressed neutrophil infiltration and myeloperoxidase activity, and inhibited NFkappaB and p38 mitogen-activated protein kinase activation in the lung. These results prove the value of inhaled mannosylated liposomes as powerful targeting systems for the delivery of anti-inflammatory drugs to alveolar macrophages to improve their efficacy against lung inflammation.
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Wassana
authors.initials: W
authors.lastname: Wijagkanalan
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawakami
authors.forename: Mugen
authors.initials: M
authors.lastname: Teshima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sasaki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D008070:Lipopolysaccharides / Q000633:toxicity*; D008081:Liposomes; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008358:Mannose / Q000737:chemistry*; D011014:Pneumonia / Q000139:chemically induced* / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D008081:Liposomes; D003907:Dexamethasone; D008358:Mannose