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MPB-07 Reduces the Inflammatory Response to Pseudomonas aeruginosa in Cystic Fibrosis Bronchial Cells

Laboratory of Molecular Pathology, Cystic Fibrosis Center, and Laboratory of Clinical Immunology, University Hospital of Verona; Department of Pathology, University of Verona, Verona, Italy; Institut de Physiologie et Biologie Cellulaires CNRS, Université de Poitiers, Poitiers, France; Department of Biochemistry and Molecular Biology. University of Ferrara, Ferrara, Italy

Correspondence and requests for reprints should be addressed to Maria Cristina Dechecchi, Laboratory of Molecular Pathology—Cystic Fibrosis Center, Azienda Ospedaliera di Verona-Piazzale Stefani 1, 37126, Verona, Italy. E-mail: cristina.dechecchi{at}azosp.vr.it

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 F508 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 F508 CFTR corrector MPB-07 produces an antiinflammatory effect in CF bronchial cells exposed to P. aeruginosa in vitro.

Key Words: cystic fibrosis • inflammation • Pseudomonas aeruginosa

CLINICAL RELEVANCE MPB-07 is presented here as a useful tool to investigate the proinflammatory phenotype and to develop successful therapies targeted at the modulation of the detrimental effects of innate immunity observed in CF lungs.

 

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