Liposome-encapsulated dexamethasone attenuates ventilator-induced lung inflammation

M. A. Hegeman, P. M. Cobelens, J. A. A. M. Kamps, M. P. Hennus, N. J. G. Jansen, M. J. Schultz, A. J. van Vught, G. Molema, C. J. Heijnen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

BACKGROUND AND PURPOSE

Systemic glucocorticoid therapy may effectively attenuate lung inflammation but also induce severe side-effects. Delivery of glucocorticoids by liposomes could therefore be beneficial. We investigated if liposome-encapsulated dexamethasone inhibited ventilator-induced lung inflammation. Furthermore, we evaluated whether targeting of cellular Fc gamma-receptors (Fc gamma Rs) by conjugating immunoglobulin G (IgG) to liposomes, would improve the efficacy of dexamethasone-liposomes in attenuating granulocyte infiltration, one of the hallmarks of lung inflammation.

EXPERIMENTAL APPROACH

Mice were anaesthetized, tracheotomized and mechanically ventilated for 5 h with either 'low' tidal volumes similar to 7.5 mL center dot kg-1 (LVT) or 'high' tidal volumes similar to 15 mL center dot kg-1 (HVT). At initiation of ventilation, we intravenously administered dexamethasone encapsulated in liposomes (Dex-liposomes), dexamethasone encapsulated in IgG-modified liposomes (IgG-Dex-liposomes) or free dexamethasone. Non-ventilated mice served as controls.

KEY RESULTS

Dex-liposomes attenuated granulocyte infiltration and IL-6 mRNA expression after LVT-ventilation, but not after HVT-ventilation. Dex-liposomes also down-regulated mRNA expression of IL-1 beta and KC, but not of CCL2 (MCP-1) in lungs of LVT and HVT-ventilated mice. Importantly, IgG-Dex-liposomes inhibited granulocyte influx caused by either LVT or HVT-ventilation. IgG-Dex-liposomes diminished IL-1 beta and KC mRNA expression in both ventilation groups, and IL-6 and CCL2 mRNA expression in the LVT-ventilated group. Free dexamethasone prevented granulocyte influx and inflammatory mediator expression induced by LVT or HVT-ventilation.

CONCLUSIONS AND IMPLICATIONS

Fc gamma R-targeted IgG-Dex-liposomes are pharmacologically more effective than Dex-liposomes particularly in inhibiting pulmonary granulocyte infiltration. IgG-Dex-liposomes inhibited most parameters of ventilator-induced lung inflammation as effectively as free dexamethasone, with the advantage that liposome-encapsulated dexamethasone will be released locally in the lung thereby preventing systemic side-effects.

Original languageEnglish
Pages (from-to)1048-1058
Number of pages11
JournalBritish Journal of Pharmacology
Volume163
Issue number5
DOIs
Publication statusPublished - Jul-2011

Keywords

  • mechanical ventilation
  • ventilator-induced lung injury
  • lung inflammation
  • Fc gamma-receptor targeting
  • dexamethasone-liposomes
  • mouse
  • MECHANICAL VENTILATION
  • CYTOKINE RELEASE
  • IN-VIVO
  • INJURY
  • ACTIVATION
  • RATS
  • CORTICOSTEROIDS
  • PERMEABILITY
  • PRESSURES
  • HYPEROXIA

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