title: Azithromycin and clarithromycin inhibit lipopolysaccharide-induced murine pulmonary neutrophilia mainly through effects on macrophage-derived granulocyte-macrophage colony-stimulating factor and interleukin-1beta.
abstract: Macrolide antibiotics possess immunomodulatory/anti-inflammatory properties. These properties are considered fundamental for the efficacy of macrolide antibiotics in the treatment of chronic inflammatory diseases like diffuse panbronchiolitis and cystic fibrosis. However, the molecular mechanisms and cellular targets of anti-inflammatory/immunomodulatory macrolide activity are still not fully understood. To describe anti-inflammatory effects of macrolides in more detail and to identify potential biomarkers of their activity, we have investigated the influence of azithromycin and clarithromycin on the inflammatory cascade leading to neutrophil infiltration into lungs after intranasal lipopolysaccharide challenge in mice. Azithromycin and clarithromycin pretreatment reduced total cell and neutrophil numbers in bronchoalveolar lavage fluid and myeloperoxidase concentration in lung tissue. In addition, concentrations of several inflammatory mediators, including CCL2, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-1beta (IL-1beta), tumor necrosis factor alpha, and sE-selectin in lung homogenates were decreased after macrolide treatment. Inhibition of cytokine production observed in vivo was also corroborated in vitro in lipopolysaccharide-stimulated monocytes/macrophages, but not in an epithelial cell line. In summary, results presented in this article confirm that macrolides can suppress neutrophil-dominated pulmonary inflammation and suggest that the effect is mediated through inhibition of GM-CSF and IL-1beta production by alveolar macrophages. Besides GM-CSF and IL-1beta, CCL2 and sE-selectin are also identified as potential biomarkers of macrolide anti-inflammatory activity in the lungs.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Limited, Croatia. martina.z.bosnar@gsk.com
authors.forename: Martina
authors.initials: M
authors.lastname: Bosnar
authors.forename: Berislav
authors.initials: B
authors.lastname: Bosnjak
authors.forename: Snjezana
authors.initials: S
authors.lastname: Cuzic
authors.forename: Boska
authors.initials: B
authors.lastname: Hrvacic
authors.forename: Nikola
authors.initials: N
authors.lastname: Marjanovic
authors.forename: Ines
authors.initials: I
authors.lastname: Glojnaric
authors.forename: Ognjen
authors.initials: O
authors.lastname: Culic
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parnham
authors.forename: Vesna
authors.initials: V
authors.lastname: Erakovic Haber
mesh_terms: D000818:Animals; D017963:Azithromycin / Q000494:pharmacology*; D002460:Cell Line; D017291:Clarithromycin / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology / Q000633:toxicity; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008168:Lung / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017963:Azithromycin; D017291:Clarithromycin