Cystic fibrosis (CF) lung disease is characterized by progressive chronic infection and inflammation of the airways representing the major cause of mortality in patients. Current anti-inflammatory strategies for the treatment of pulmonary disease in CF are limited; thus, there is continued interest in identifying additional molecular targets for therapeutic intervention. Several pieces of evidences highlight the role of sphingolipids (SLs) in CF. In fact, ceramide accumulation has been demonstrated in lower airway of CF patients (Brodlie M, et al. Am J Respir Crit Care Med. 2010;182:369-75). Moreover, the infection of bronchial epithelial cells with Pseudomonas aeruginosa (PAO) activated host acid sphingomyelinase leading to ceramide generation at the cell surface, which regulates the release of inflammatory cytokines, as IL-8 (Grassmé H, et al. Nat Med. 2003;9(3):322-30). In addition, miglustat, a well-characterized iminosugar-based inhibitor of β-glucosidase 2 (GBA2), has shown promise in CF treatment because it reduces the inflammatory response to infection by PAO and restores F508del-CFTR chloride channel activity even if the molecular mechanism involved is unknown so far (Loberto N, et al. PLoS One. 2014;9:e104763). Taking into account this evidence, the aim of our study was to investigate the molecular mechanism linking GBA2 and the inflammatory response in CF cells. Our experiments were performed on both a human CF bronchial epithelial cell line as well as in human primary bronchial cells. Using these experimental models, we found that the major part of the ceramide produced at the cell plasma membrane level of CF bronchial epithelial cells, subjected to PAO infection, derives from the action of GBA2. These data were also confirmed by the use of a potent inhibitor of GBA2, N-(5adamantane-1-yl-methoxy)pentyl)- deoxynojirimycin (Genz529648). We also examined the impact of lowering the expression of GBA2 in human CF bronchial epithelial cells exposed to P. aeruginosa using siRNA oligonucleotides. Interestingly, we found that basal IL-8 expression and release is reduced in both uninfected and infected cells by PAO. In conclusion, our study proposes GBA2 as a novel target to reduce the pro-inflammatory response to PAO in CF bronchial cells. These results further support the use of modulators of SL metabolism to treat CF lung inflammation.
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|Titolo:||INVOLVEMEMENT OF GBA2 IN THE INFLAMMATORY RESPONSE TO PSEUDOMONAS AERUGINOSA IN CYSTIC FIBROSIS|
|Data di pubblicazione:||2015|
|Appare nelle tipologie:||04.3 Abstract (Riassunto) in convegno in Rivista/Volume|