A novel macrolide solithromycin exerts superior anti-inflammatory effect via NF-κB inhibition.
Macrolides are reported to reduce exacerbation of chronic inflammatory respiratory disease, such as chronic obstructive pulmonary disease (COPD), and also show anti-inflammatory effects in vitro and in vivo. However the anti-inflammatory efficacies of current macrolides are relatively weak. Here we found that a novel macrolide/fluoroketolide solithromycin (CEM-101) showed superior anti-inflammatory effects to macrolides in current clinical use. The effects of solithromycin (SOL) on lipopolysaccharide-induced TNFα (tumor necrosis factor α) and/or CXCL8 (C-X-C motif chemokine ligand 8; interleukin-8) release, phorbol 12-myristate 13-acetate-induced MMP9 (matrix metalloproteinase 9) activity and NF-κB (nuclear factor-κB) activity under conditions of oxidative stress have been evaluated and compared with the effects of erythromycin, clarithromycin, azithromycin, and telithromycin in macrophage-like PMA-differentiated U937 cells and peripheral blood mononuclear cells (PBMC) obtained from COPD patients. We also examined effect of SOL on cigarette smoke-induced airway inflammation in mice. SOL exerted superior inhibitory effects on TNFα/CXCL8 production and MMP9 activity in monocytic U937 cells. In addition, SOL suppressed TNFα release and MMP9 activity in PBMC from COPD patients at 10 µM, which is 10 times more potent than the other macrolides tested. Activated NF-κB by oxidative stress was completely reversed by SOL. SOL also inhibited cigarette smoke-induced neutrophilia and pro-MMP9 production in vivo, although erythromycin did not inhibit them. Thus, SOL showed better anti-inflammatory profiles compared with macrolides currently used in the clinic and may be a promising anti-inflammatory and antimicrobial macrolide for the treatment of COPD in future.
Airway Disease Section, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Royal Brompton Campus, Dovehouse Street, London SW3 6LY.
Yoshiki
Y
Kobayashi
Hiroo
H
Wada
Christos
C
Rossios
Dai
D
Takagi
Manabu
M
Higaki
Shin'ichiro
S
Mikura
Hajime
H
Goto
Peter J
PJ
Barnes
Kazuhiro
K
Ito
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D018384:Oxidative Stress / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects; D014230:Triazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D016209:Interleukin-8; D018942:Macrolides; D016328:NF-kappa B; D014028:Tobacco Smoke Pollution; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C547755:solithromycin; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9