title: Roxithromycin inhibits VEGF-induced human airway smooth muscle cell proliferation: Opportunities for the treatment of asthma.
abstract: Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodelling, which is associated with increased airway smooth muscle (ASM) mass. Roxithromycin (RXM) has been widely used in asthma treatment; however, its mechanism of action is poorly understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodelling in patients with asthma, and shown to promote ASM cell proliferation. Here, we investigated the effect of RXM on VEGF-induced ASM cell proliferation and attempted to elucidate the underlying mechanisms of action. We tested the effect of RXM on proliferation and cell cycle progression, as well as on the expression of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), phospho-Akt, and caveolin-1 in VEGF-stimulated ASM cells. RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed by inhibiting the activity of ERK1/2, but not that of Akt. Furthermore, RXM treatment inhibits VEGF-induced activation of VEGFR2 and ERK and downregulation of caveolin-1 in a dose-dependent manner. RXM also inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. Collectively, our findings suggest that RXM inhibits VEGF-induced ASM cell proliferation by suppression of VEGFR2 and ERK1/2 activation and caveolin-1 down-regulation, which may be involved in airway remodelling. Further elucidation of the mechanisms underlying these observations should enable the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma.
authors: Department of Radiology, Tianjin Hospital of Integrated Traditional Chinese and Western Medicine, Tianjin, China. Electronic address: 34713316@qq.com.
authors: Qing-Mei
authors: QM
authors: Pei
authors: Department of Respiration, Tianjin First Central Hospital, Tianjin, China. Electronic address: jiangping@163.com.
authors: Ping
authors: P
authors: Jiang
authors: Department of Respiration, Tianjin First Central Hospital, Tianjin, China. Electronic address: YangMin@163.com.
authors: Min
authors: M
authors: Yang
authors: Department of Respiration, Tianjin First Central Hospital, Tianjin, China. Electronic address: qianxuejiao@163.com.
authors: Xue-Jiao
authors: XJ
authors: Qian
authors: Department of Respiration, Tianjin First Central Hospital, Tianjin, China. Electronic address: LJB1984@163.com.
authors: Jiang-Bo
authors: JB
authors: Liu
authors: Department of Respiration, Tianjin First Central Hospital, Tianjin, China. Electronic address: chenghao0726@hotmail.com.
authors: Sung-Ho
authors: SH
authors: Kim
mesh_terms: D001249:Asthma / Q000188:drug therapy* / Q000473:pathology*; D051242:Caveolin 1 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D015575:Roxithromycin / Q000494:pharmacology* / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D015575:Roxithromycin; D040301:Vascular Endothelial Growth Factor Receptor-2; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Airway remodelling; Akt; ERK1/2; Roxithromycin; VEGF