Received for publication July 2, 2008.
Revised July 28, 2008.
Accepted for publication July 28, 2008.

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 NFB, production of cytokines and chemokines, and neutrophil activation. Although glucocorticoids are the drugs of choice, administration of free drugs results in adverse effects due to lack of selectivity for the inflammatory effector cells. Since 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 previously demonstrated 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 (DP) 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-1 beta and cytokine-induced neutrophil chemoattractant-1 levels, suppressed neutrophil infiltration as well as myeloperoxidase activity, and inhibited NFB and p38MAPK 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.

Key words: Tumor necrosis factor, Glucorticoids/Mineralocorticoids, P38 MAP Kinase, NFkappaB, Liposome, Receptor-mediated