Investigation on novel targets for the treatment of Cystic Fibrosis (CF) lung inflammation is a major priority, considering that no effective therapy is available for this purpose. Consistently with the evidence that the sphingolipid (SL) ceramide regulates airway inflammation and infection in CF mice and patients, SLs have been identified as targets to treat pulmonary disorders, including CF. Because miglustat, an inhibitor of the synthesis of glycosphingolipids, reduces the P.aeruginosa-dependent transcription of IL-8 gene in bronchial cells, we examined the effect of miglustat and amitriptyline, another drug affecting ceramide metabolism, on expression of 92 genes implicated in host immune defence. Infection with P.aeruginosa strain PAO1 up-modulated the expression of 14 (27%) genes in IB3-1 cells and 15 (29%) in CF primary respiratory epithelium grown at air-liquid interface, including chemokines (IL-8, Gro-α/β/γ, GCP-2), pro-inflammatory citokines (IL-1α/β, IL-6, TNF-α, ICAM-1, NFKB1, TLR-2 and HBD-4 genes, confirming that bronchial epithelium is an important source of inflammatory mediators. Both miglustat and amitriptyline reduced the immune response, an effect that went in parallel with a decrease in P.aeruginosa-induced ceramide accumulation. Miglustat (100mg/Kg), given to C57BL/6 mice once daily for a period of three consecutive days before lipopolysaccharide (LPS) challenge, strongly reduced the amount of neutrophils recruited in the airways and the expression of the chemokine KC in lung extracts. Collectively these results indicate that targeting SLs metabolism can down-modulate the recruitment of neutrophils into the lung.
Modulators of Sphingolipid Metabolism Reduce Lung Inflammation
LAMPRONTI, Ilaria;GAMBARI, Roberto;
2011
Abstract
Investigation on novel targets for the treatment of Cystic Fibrosis (CF) lung inflammation is a major priority, considering that no effective therapy is available for this purpose. Consistently with the evidence that the sphingolipid (SL) ceramide regulates airway inflammation and infection in CF mice and patients, SLs have been identified as targets to treat pulmonary disorders, including CF. Because miglustat, an inhibitor of the synthesis of glycosphingolipids, reduces the P.aeruginosa-dependent transcription of IL-8 gene in bronchial cells, we examined the effect of miglustat and amitriptyline, another drug affecting ceramide metabolism, on expression of 92 genes implicated in host immune defence. Infection with P.aeruginosa strain PAO1 up-modulated the expression of 14 (27%) genes in IB3-1 cells and 15 (29%) in CF primary respiratory epithelium grown at air-liquid interface, including chemokines (IL-8, Gro-α/β/γ, GCP-2), pro-inflammatory citokines (IL-1α/β, IL-6, TNF-α, ICAM-1, NFKB1, TLR-2 and HBD-4 genes, confirming that bronchial epithelium is an important source of inflammatory mediators. Both miglustat and amitriptyline reduced the immune response, an effect that went in parallel with a decrease in P.aeruginosa-induced ceramide accumulation. Miglustat (100mg/Kg), given to C57BL/6 mice once daily for a period of three consecutive days before lipopolysaccharide (LPS) challenge, strongly reduced the amount of neutrophils recruited in the airways and the expression of the chemokine KC in lung extracts. Collectively these results indicate that targeting SLs metabolism can down-modulate the recruitment of neutrophils into the lung.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
