Liposome‐encapsulated dexamethasone attenuates ventilator‐induced lung inflammation

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 Fcγ‐receptors (FcγRs) 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 ∼7.5 mL·kg⁻¹ (LV_T) or ‘high’ tidal volumes ∼15 mL·kg⁻¹ (HV_T). 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 LV_T‐ventilation, but not after HV_T‐ventilation. Dex‐liposomes also down‐regulated mRNA expression of IL‐1β and KC, but not of CCL2 (MCP‐1) in lungs of LV_T and HV_T‐ventilated mice. Importantly, IgG‐Dex‐liposomes inhibited granulocyte influx caused by either LV_T or HV_T‐ventilation. IgG‐Dex‐liposomes diminished IL‐1β and KC mRNA expression in both ventilation groups, and IL‐6 and CCL2 mRNA expression in the LV_T‐ventilated group. Free dexamethasone prevented granulocyte influx and inflammatory mediator expression induced by LV_T or HV_T‐ventilation.

CONCLUSIONS AND IMPLICATIONS FcγR‐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.

DOI: 10.1111/j.1476-5381.2011.01314.x

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