title: Anti-inflammatory effect of miglustat in bronchial epithelial cells.
abstract: The role of CFTR deficiency in promoting inflammation remains unclear. Perez et al. [A. Perez, A.C. Issler, C.U. Cotton, T.J. Kelley, A.S. Verkman and P.B. Davis, CFTR inhibition mimics the cystic fibrosis inflammatory profile. Am J Physiol Lung Cell Mol Physiol 2007; 292:L383-L395.] recently demonstrated that the inhibition of function of w/t CFTR produces an inflammatory profile that resembles that observed in CF patients, whereas we found that correction of F508del-CFTR function with MPB-07 down-modulates the inflammatory response to P. aeruginosa in CF bronchial cells [M.C. Dechecchi, E. Nicolis, V. Bezzerri, A. Vella, M. Colombatti, B.M. Assael, et al., MPB-07 reduces the inflammatory response to Pseudomonas aeruginosa in cystic fibrosis bronchial cells. Am J Respir Cell Mol Biol 2007; 36, 615-624.]. Since both evidence support a link between CFTR function and inflammation, we extended our investigation to other F508del-CFTR correctors, such as miglustat (Norez, 2006), an approved drug for Gaucher disease, in comparison with the galactose analogue NB-DGJ. We report here that miglustat but not NB-DGJ restores F508del-CFTR function in CF bronchial epithelial IB3-1 and CuFi-1 cells. Miglustat and NB-DGJ reduce the inflammatory response to P. aeruginosa in both CF and non-CF bronchial cells, indicating that the anti-inflammatory effect is independent of the correction of F508del-CFTR function. Miglustat also inhibits the inflammatory response induced by the supernatant of mucopurulent material obtained from the lower airway tract of cystic fibrosis patients with chronic bacterial colonization (Ribeiro, 2005). Both compounds do not interfere with the adherence of P. aeruginosa to the cells and reduce the expression of IL-8 not only after challenge with P. aeruginosa but also after exposure to TNF alpha or IL-1 beta, suggesting an effect on transduction proteins downstream and in common with different receptors for pathogens. Finally, miglustat has no major effects on overall binding activity of transcription factors NF-kappaBNF-kB and AP-1. Since miglustat is an approved drug, it could be investigated as a novel anti-inflammatory molecule to ameliorate lung inflammation in CF patients.
authors.affiliation: Laboratory of Molecular Pathology, Laboratory of Clinical Chemistry and Haematology, University Hospital of Verona, Verona, Italy. cristina.dechecchi@azosp.vr.it
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Dechecchi
authors.forename: Elena
authors.initials: E
authors.lastname: Nicolis
authors.forename: Caroline
authors.initials: C
authors.lastname: Norez
authors.forename: Valentino
authors.initials: V
authors.lastname: Bezzerri
authors.forename: Monica
authors.initials: M
authors.lastname: Borgatti
authors.forename: Irene
authors.initials: I
authors.lastname: Mancini
authors.forename: Paolo
authors.initials: P
authors.lastname: Rizzotti
authors.forename: Carla M P
authors.initials: CM
authors.lastname: Ribeiro
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
authors.forename: Frederic
authors.initials: F
authors.lastname: Becq
authors.forename: Giulio
authors.initials: G
authors.lastname: Cabrini
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000473:pathology; D018929:Cell Culture Techniques; D002460:Cell Line; D003550:Cystic Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D021381:Protein Transport; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: C505032:CFTR protein, human; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017485:1-Deoxynojirimycin; C059896:miglustat