title: MPB-07 reduces the inflammatory response to Pseudomonas aeruginosa in cystic fibrosis bronchial cells.
abstract: Chronic lung inflammation in cystic fibrosis (CF) is specifically characterized by predominant endobronchial neutrophil infiltrates, colonization by Pseudomonas aeruginosa, and elevated levels of cytokines and chemokines, first of all IL-8. The extensive inflammatory process in CF lungs is the basis of progressive tissue damage and is largely considered detrimental, making antiinflammatory approaches a relevant therapeutic target. This neutrophil-dominated inflammation seems to be related to an excessive proinflammatory signaling, originating from the same surface epithelial cells expressing the defective CF transmembrane conductance regulator (CFTR) protein, although the underlying mechanisms have not been completely elucidated. To investigate the relationship between defective CFTR and the inflammatory response to P. aeruginosa in CF airway cells, we studied the effect of the DeltaF508 CFTR corrector, benzo(c)quinolizinium (MPB)-07 (Dormer et al., J Cell Science 2001;114:4073-4081). CF bronchial epithelial IB3-1 and CuFi-1 cells overproduced the inflammatory molecules, IL-8 and intercellular adhesion molecule (ICAM)-1, in response to P. aeruginosa, compared with the wild-type, CFTR-expressing bronchial cells, S9, and NuLi-1 cells. In both IB3-1 and CuFi-1 cells, the corrector MPB-07 dramatically reduces the IL-8 and ICAM-1 mRNA expression elicited by P. aeruginosa infection. Correction of CFTR-dependent Cl- efflux was confirmed in MPB-07-treated IB3-1 and CuFi-1 cells. In conclusion, the DeltaF508 CFTR corrector MPB-07 produces an antiinflammatory effect in CF bronchial cells exposed to P. aeruginosa in vitro.
authors.affiliation: Laboratory of Molecular Pathology-Cystic Fibrosis Center, and Department of Pathology, University Hospital of 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: Valentino
authors.initials: V
authors.lastname: Bezzerri
authors.forename: Antonio
authors.initials: A
authors.lastname: Vella
authors.forename: Marco
authors.initials: M
authors.lastname: Colombatti
authors.forename: Baroukh Maurice
authors.initials: BM
authors.lastname: Assael
authors.forename: Yvette
authors.initials: Y
authors.lastname: Mettey
authors.forename: Monica
authors.initials: M
authors.lastname: Borgatti
authors.forename: Irene
authors.initials: I
authors.lastname: Mancini
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: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001980:Bronchi / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D002712:Chlorides / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D011807:Quinolizines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C451901:6-hydroxy-10-chlorobenzo(c)quinolizinium; D000893:Anti-Inflammatory Agents; D002712:Chlorides; D016209:Interleukin-8; D016328:NF-kappa B; D011807:Quinolizines; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D018799:Intercellular Adhesion Molecule-1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019833:Genistein; D000242:Cyclic AMP