title: Levofloxacin reduces inflammatory cytokine levels in human bronchial epithelia cells: implications for aerosol MP-376 (levofloxacin solution for inhalation) treatment of chronic pulmonary infections.
abstract: Inflammation resulting from chronic bacterial infection in the lung contributes to long-term pulmonary complications in chronic pulmonary infections such as cystic fibrosis. Aerosol administration of levofloxacin as in the form of the investigational formulation MP-376 results in higher concentrations in lung tissues that are higher than those that can be attained with oral or intravenous dosing of levofloxacin. The objective of this study was to evaluate the effect of high concentrations of levofloxacin achieved with aerosol administration of MP-376 on proinflammatory cytokine secretion by immortalized human bronchial epithelia cells in vitro. Additionally, we investigated the potential mechanisms of the immunomodulatory effect of levofloxacin. In vitro studies in human lung epithelial cell lines showed that levofloxacin led to a dose-related reduction in IL-6 and IL-8 concentrations, with 300 μg mL(-1) resulting in the reduction of levels of IL-6 by fourfold and IL-8 by twofold (P<0.05); in contrast, tobramycin increased IL-6 levels by 50%, but had no effect on IL-8. Levofloxacin treatment did not affect the cytokine mRNA level and nuclear factor-κB-dependent promoter activity. These findings suggest that high concentrations of levofloxacin obtained in pulmonary tissues following the administration of aerosol MP-376 may provide additional benefits in patients with chronic pulmonary infections that are independent of its antibacterial properties.
authors.affiliation: MPEX Pharmaceuticals, San Diego, CA, USA. rtsivkovski@mpexpharma.com
authors.forename: Ruslan
authors.initials: R
authors.lastname: Tsivkovskii
authors.forename: Mojgan
authors.initials: M
authors.lastname: Sabet
authors.forename: Ziad
authors.initials: Z
authors.lastname: Tarazi
authors.forename: David C
authors.initials: DC
authors.lastname: Griffith
authors.forename: Olga
authors.initials: O
authors.lastname: Lomovskaya
authors.forename: Michael N
authors.initials: MN
authors.lastname: Dudley
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000008:administration & dosage; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D002908:Chronic Disease; D004847:Epithelial Cells / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064704:Levofloxacin; D015242:Ofloxacin / Q000008:administration & dosage / Q000494:pharmacology*; D011014:Pneumonia / Q000188:drug therapy; D014031:Tobramycin / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
chemical_list: D000336:Aerosols; D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D016209:Interleukin-8; D064704:Levofloxacin; D015242:Ofloxacin; D014031:Tobramycin; D000093242:Interleukin-6 Inhibitors