Liposome‐encapsulated dexamethasone attenuates ventilator‐induced lung inflammation

Abstract

BACKGROUND AND PURPOSESystemic 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 Fcg-receptors (FcgRs) 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 APPROACHMice were anaesthetized, tracheotomized and mechanically ventilated for 5 h with either 'low' tidal volumes~7.5 mL·kg -1 (LVT) or 'high' tidal volumes~15 mL·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 RESULTSDex-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-1b 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 HVTventilation. IgG-Dex-liposomes diminished IL-1b 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 IMPLICATIONSFcgR-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. AbbreviationsALI, acute lung

Ventilator-Induced Lung Injury: Mechanisms and Future Therapeutic Interventions

“…We observed that administration of Dex-liposomes at initiation of ventilation diminished crucial inflammatory parameters of VILI such as IL-1 , IL-6 and KC mRNA expression, especially in LV T -ventilated mice (Hegeman et al, 2011a). Yet, this formulation was not as effective as free dexamethasone in preventing granulocyte infiltration into pulmonary tissue (Hegeman et al, 2011a). As granulocytes are considered to be important in the development of VILI (Kawano et al, 1987), we hypothesized that phagocytosis of liposomes by activated granulocytes may be advantageous and should therefore be enhanced (Hegeman et al, 2011a).…”

“…Yet, this formulation was not as effective as free dexamethasone in preventing granulocyte infiltration into pulmonary tissue (Hegeman et al, 2011a). As granulocytes are considered to be important in the development of VILI (Kawano et al, 1987), we hypothesized that phagocytosis of liposomes by activated granulocytes may be advantageous and should therefore be enhanced (Hegeman et al, 2011a). We proposed that IgG-modified Dex-liposomes (IgG-Dex-liposomes) may be more efficient in attenuating ventilator-induced lung inflammation than Dex-liposomes due to interaction with Fc -receptors (Fc Rs) on activated granulocytes and macrophages (McKenzie & Schreiber, 1998).…”

“…Because local delivery of glucocorticoids by liposomal formulations could be of therapeutic importance in the context of VILI as well, we studied whether liposomes containing dexamethasone (Dexliposomes) inhibited ventilator-induced lung inflammation (Hegeman et al, 2011a). We observed that administration of Dex-liposomes at initiation of ventilation diminished crucial inflammatory parameters of VILI such as IL-1 , IL-6 and KC mRNA expression, especially in LV T -ventilated mice (Hegeman et al, 2011a). Yet, this formulation was not as effective as free dexamethasone in preventing granulocyte infiltration into pulmonary tissue (Hegeman et al, 2011a).…”

“…We proposed that IgG-modified Dex-liposomes (IgG-Dex-liposomes) may be more efficient in attenuating ventilator-induced lung inflammation than Dex-liposomes due to interaction with Fc -receptors (Fc Rs) on activated granulocytes and macrophages (McKenzie & Schreiber, 1998). Indeed, IgG-Dex-liposomes were pharmacologically more effective than Dex-liposomes particularly in preventing granulocyte infiltration induced by either LV T or HV T -ventilation (Hegeman et al, 2011a). Additionally, IgG-Dex-liposomes inhibited most parameters of ventilator-induced lung inflammation as efficient as free dexamethasone.…”

“…Previously, Ásgeirsdóttir et al clearly showed that delivery of liposomeencapsulated dexamethasone inhibits pro-inflammatory gene expression without affecting blood glucose levels (Asgeirsdottir et al, 2007), one of the first clinically relevant side effects of free dexamethasone treatment (Feldman-Billard et al, 2006;Weinstein et al, 1995). Because local delivery of glucocorticoids by liposomal formulations could be of therapeutic importance in the context of VILI as well, we studied whether liposomes containing dexamethasone (Dexliposomes) inhibited ventilator-induced lung inflammation (Hegeman et al, 2011a). We observed that administration of Dex-liposomes at initiation of ventilation diminished crucial inflammatory parameters of VILI such as IL-1 , IL-6 and KC mRNA expression, especially in LV T -ventilated mice (Hegeman et al, 2011a).…”