title: Azithromycin analogue CSY0073 attenuates lung inflammation induced by LPS challenge.
abstract: OBJECTIVE
  Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulating effects. Long-term azithromycin therapy in patients with chronic lung diseases such as cystic fibrosis has been associated with increased antimicrobial resistance, emergence of hypermutable strains, ototoxicity and cardiac toxicity. The aim of this study was to assess the anti-inflammatory effects of the non-antibiotic azithromycin derivative CSY0073.
  
  
  METHODS
  We compared the effects of CSY0073 with those of azithromycin in experiments on bacterial cultures, Pseudomonas aeruginosa biofilm, lung cells and mice challenged intranasally with P. aeruginosa LPS.
  
  
  RESULTS
  In contrast to azithromycin, CSY0073 did not inhibit the growth of P. aeruginosa, Staphylococcus aureus or Haemophilus influenzae and had no effect on an established P. aeruginosa biofilm. Bronchoalveolar lavage (BAL) fluids and lung homogenates collected after the LPS challenge in mice showed that CSY0073 and azithromycin (200 mg·kg(-1), i.p.) decreased neutrophil counts at 24 h and TNF-α, CXCL1 and CXCL2 levels in the BAL fluid after 3 h and IL-6, CXCL2 and IL-1β levels in the lung after 3 h compared with the vehicle. However, only azithromycin reduced IL-1β levels in the lung 24 h post LPS challenge. CSY0073 and azithromycin similarly diminished the production of pro-inflammatory cytokines by macrophages, but not lung epithelial cells, exposed to P. aeruginosa LPS.
  
  
  CONCLUSIONS
  Unlike azithromycin, CSY0073 had no antibacterial effects but it did have a similar anti-inflammatory profile to that of azithromycin. Hence, CSY0073 may have potential as a long-term treatment for patients with chronic lung diseases.
authors.affiliation: INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France; Inserm U874, Paris, France; Unité de défense Innée et Inflammation, Institut Pasteur, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Balloy
authors.forename: A
authors.initials: A
authors.lastname: Deveaux
authors.forename: D
authors.initials: D
authors.lastname: Lebeaux
authors.forename: O
authors.initials: O
authors.lastname: Tabary
authors.forename: P
authors.initials: P
authors.lastname: le Rouzic
authors.forename: J M
authors.initials: JM
authors.lastname: Ghigo
authors.forename: P F
authors.initials: PF
authors.lastname: Busson
authors.forename: P Y
authors.initials: PY
authors.lastname: Boëlle
authors.forename: J Guez
authors.initials: JG
authors.lastname: Guez
authors.forename: U
authors.initials: U
authors.lastname: Hahn
authors.forename: A
authors.initials: A
authors.lastname: Clement
authors.forename: M
authors.initials: M
authors.lastname: Chignard
authors.forename: H
authors.initials: H
authors.lastname: Corvol
authors.forename: M
authors.initials: M
authors.lastname: Burnet
authors.forename: L
authors.initials: L
authors.lastname: Guillot
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; C568293:CSY 0073; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D017963:Azithromycin
keywords: COPD; cystic fibrosis; lung inflammation; macrolides