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Research ArticleArticle

Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model

Wassana Wijagkanalan, Yuriko Higuchi, Shigeru Kawakami, Mugen Teshima, Hitoshi Sasaki and Mitsuru Hashida
Molecular Pharmacology November 2008, 74 (5) 1183-1192; DOI: https://doi.org/10.1124/mol.108.050153
Wassana Wijagkanalan
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Yuriko Higuchi
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Shigeru Kawakami
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Mugen Teshima
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Hitoshi Sasaki
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Mitsuru Hashida
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Abstract

Inhalation of bacterial endotoxin induces pulmonary inflammation by activation of nuclear factor κB (NFκB), 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 α, interleukin-1β, and cytokine-induced neutrophil chemoattractant-1 levels, suppressed neutrophil infiltration and myeloperoxidase activity, and inhibited NFκB 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.

Footnotes

  • This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by Health and Labor Sciences Research Grants for Research on Advanced Medical Technology from the Ministry of Health, Labor and Welfare of Japan.

  • ABBREVIATIONS: LPS, lipopolysaccharide; BAL, bronchoalveolar lavage; Chol, cholesterol; Dex, dexamethasone; DP, dexamethasone palmitate; DPBL, dexamethasone palmitate containing bare liposomes; DPML, dexamethasone palmitate containing mannosylated liposomes; DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine; Man-C4-Chol, cholesten-5-yloxy-N(4-((1-imino-2-d-thiomannosylethyl)amino)alkyl)formamide; NFκB, nuclear factor κB; MAPK, mitogen-activated protein kinase; TNFα, tumor necrosis factor α; IL-1β, interleukin-1β; CINC-1, cytokine-induced neutrophil chemoattractant-1; GC, glucocorticoid; MPO, myeloperoxidase; HPLC, high-performance liquid chromatography; PBS, phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay; EMSA, electrophoretic mobility shift assay; H/E, hematoxylin/eosin; Man-liposomes, mannosylated liposomes.

    • Received July 2, 2008.
    • Accepted July 28, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (5)
Molecular Pharmacology
Vol. 74, Issue 5
1 Nov 2008
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Research ArticleArticle

Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model

Wassana Wijagkanalan, Yuriko Higuchi, Shigeru Kawakami, Mugen Teshima, Hitoshi Sasaki and Mitsuru Hashida
Molecular Pharmacology November 1, 2008, 74 (5) 1183-1192; DOI: https://doi.org/10.1124/mol.108.050153

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Research ArticleArticle

Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model

Wassana Wijagkanalan, Yuriko Higuchi, Shigeru Kawakami, Mugen Teshima, Hitoshi Sasaki and Mitsuru Hashida
Molecular Pharmacology November 1, 2008, 74 (5) 1183-1192; DOI: https://doi.org/10.1124/mol.108.050153
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