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.