Airway Disease Section, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Royal Brompton Campus, Dovehouse Street, London SW3 6LY.
J Pharmacol Exp Ther. 2013 Apr;345(1):76-84. doi: 10.1124/jpet.112.200733. Epub 2013 Jan 28.
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.
大环内酯类药物据报道可减少慢性炎症性呼吸道疾病（如慢性阻塞性肺疾病（COPD））的恶化，并且在体外和体内也具有抗炎作用。然而，目前大环内酯类药物的抗炎功效相对较弱。在这里，我们发现一种新型大环内酯类/氟酮内酯类药物 solithromycin（CEM-101）具有优于当前临床使用的大环内酯类药物的抗炎效果。评估了 solithromycin（SOL）对脂多糖诱导的 TNFα（肿瘤坏死因子α）和/或 CXCL8（C-X-C 基序趋化因子配体 8；白细胞介素-8）释放、佛波醇 12-肉豆蔻酸 13-乙酸酯诱导的 MMP9（基质金属蛋白酶 9）活性和 NF-κB（核因子-κB）活性的影响，并与巨噬细胞样 PMA 分化的 U937 细胞和 COPD 患者外周血单核细胞（PBMC）中红霉素、克拉霉素、阿奇霉素和泰利霉素的影响进行了比较。我们还检查了 SOL 对香烟烟雾诱导的小鼠气道炎症的影响。SOL 对单核细胞 U937 细胞中 TNFα/CXCL8 的产生和 MMP9 活性具有更好的抑制作用。此外，在 10 µM 时，SOL 抑制了来自 COPD 患者的 PBMC 中 TNFα 的释放和 MMP9 活性，其效力是其他测试的大环内酯类药物的 10 倍。氧化应激激活的 NF-κB 完全被 SOL 逆转。SOL 还抑制了体内香烟烟雾诱导的嗜中性粒细胞增多和前 MMP9 的产生，尽管红霉素没有抑制它们。因此，与目前临床使用的大环内酯类药物相比，SOL 显示出更好的抗炎谱，并且可能是治疗 COPD 的有前途的抗炎和抗菌大环内酯类药物。
