title: Azithromycin inhibits nuclear factor-κB activation during lung inflammation: an in vivo imaging study.
abstract: We studied in vivo the potential involvement of nuclear factor-κB (NF-κB) pathway in the molecular mechanism of the anti-inflammatory and immunomodulatory activity of azithromycin in the lung. Mice transiently transfected with the luciferase gene under the control of a NF-κB responsive element were used to assess in vivo NF-κB activation by bioluminescence imaging. Bioluminescence as well as inflammatory cells and concentrations of proinflammatory cytokines in bronchoalveolar lavage fluids, were monitored in an acute model of pulmonary inflammation resulting from intratracheal instillation of lipopolysaccharide. Lipopolysaccharide (LPS) instillation induced a marked increase in lung bioluminescence in mice transiently transfected with the luciferase gene under the control of an NF-κB responsive element, with significant luciferase expression in resident cells such as endothelial and epithelial cells, as assessed by duoplex immunofluorescence staining. Activation of NF-κB and inflammatory cell lung infiltration linearly correlated when different doses of bortezomib were used to inhibit NF-κB activation. Pretreatment with azithromycin significantly decreased lung bioluminescence and airways cell infiltration induced by LPS, also reducing proinflammatory cytokines concentrations in bronchoalveolar lavages and inhibiting NF-κB nuclear translocation. The results obtained using a novel approach to monitor NF-κB activation, provided, for the first time, in vivo evidence that azithromycin treatment results in pulmonary anti-inflammatory activity associated with the inhibition of NF-κB activation in the lung.
authors.affiliation: Chiesi Farmaceutici S.p.A Parma, Italy.
authors.forename: Fabio F
authors.initials: FF
authors.lastname: Stellari
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano Milano, Italy ; Consiglio Nazionale delle Ricerche, IBIM Palermo, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sala
authors.affiliation: Dipartimento di Scienze Medico-Veterinarie, Università di Parma Parma, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Donofrio
authors.affiliation: Dipartimento di Scienze Biomediche, Biotecnologiche e Traslazionali, Università di Parma Parma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ruscitti
authors.affiliation: Chiesi Farmaceutici S.p.A Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Caruso
authors.affiliation: Chiesi Farmaceutici S.p.A Parma, Italy.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Topini
authors.affiliation: Perkin Elmer Discovery Services Hanover, Maryland.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Francis
authors.affiliation: Perkin Elmer Alameda, California.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Li
authors.affiliation: Chiesi Farmaceutici S.p.A Parma, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Carnini
authors.affiliation: Chiesi Farmaceutici S.p.A Parma, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Civelli
authors.affiliation: Chiesi Farmaceutici S.p.A Parma, Italy.
authors.forename: Gino
authors.initials: G
authors.lastname: Villetti
keywords: Acute lung inflammation; azithromycin; bioluminescence; in vivo imaging; nuclear factor-κB