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首页> 外文学位 >Cigarette Smoke Extract (CSE) Stimulates Vascular Endothelial Growth Factor (VEGF) Release by Human Lung Fibroblasts through TGF-beta1/Smad3 Pathway.
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Cigarette Smoke Extract (CSE) Stimulates Vascular Endothelial Growth Factor (VEGF) Release by Human Lung Fibroblasts through TGF-beta1/Smad3 Pathway.

机译：香烟烟雾提取物（CSE）刺激人肺成纤维细胞通过TGF-beta1 / Smad3途径释放血管内皮生长因子（VEGF）。

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摘要

RATIONALE: Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), yet pathogenic mechanisms are not fully understood. More than 3 million people died of COPD in 2005; this represented 5% of all deaths worldwide. COPD will become the third-leading cause of death worldwide by 2030. Vascular endothelial growth factor (VEGF) is one of the major regulators of endothelial cell survival and is believed to play a role in the pathogenesis of COPD. Fibroblasts are a significant source of VEGF in the lungs; however the effect of cigarette smoke on VEGF release by fibroblasts is not fully understood. We hypothesized that cigarette smoke-induced disturbance of VEGF release by human lung fibroblasts is a potential pathogenic mechanism that could contribute to COPD. METHODS: Cigarette smoke extract (CSE) was prepared by modification of the methods of Carp and Janoff (Am.Rev.Respir.Dis, 1978). Human fetal lung fibroblasts (HFL-1) were exposed to different concentrations of CSE and for different durations. VEGF release into the media was measured using ELISA. TGF-beta1/Smad3 as a potential pathway for the observed effect was also investigated using Smad3 and TGF-beta1 receptor (TbetaR1) siRNA. RESULTS: CSE-induced VEGF release by HFL-1 in concentration and time dependent manner. CSE induced Smad3 phosphorylation and nuclear translocation in HFL-1 cells. Silencing of Smad3 by siRNA not only eliminated the stimulatory effect of CSE on VEGF release but also inhibited baseline VEGF production. Suppression of TbetaR1 by the pharmacological inhibitor (SB431542) markedly reduced VEGF release by HFL-1 in response to CSE and this effect was confirmed by TbetaR1 siRNA. In contrast, Nicotine inhibited VEGF release by HFL-1 in a dose and time dependent manner. CONCLUSIONS: Our findings indicate that CSE stimulates VEGF release by lung fibroblasts and Smad3 mediates the stimulation of VEGF release. Nicotine does not account for the CSE stimulation of VEGF production in human lung fibroblasts. The ability of lung fibroblasts to produce VEGF may play a role in pathogenesis of respiratory disease.
机译：理由：香烟烟雾是造成慢性阻塞性肺疾病（COPD）的主要原因，但其致病机理尚未完全明了。 2005年，超过300万人死于COPD；这占全球所有死亡人数的5％。到2030年，COPD将成为全球第三大死亡原因。血管内皮生长因子（VEGF）是内皮细胞存活的主要调节剂之一，据信在COPD的发病机理中发挥了作用。成纤维细胞是肺中VEGF的重要来源。然而，香烟烟雾对成纤维细胞释放VEGF的作用尚不完全清楚。我们假设香烟烟雾诱导的人肺成纤维细胞释放VEGF的干扰是可能导致COPD的潜在致病机制。方法：通过改良鲤鱼和詹诺夫方法（Am.Rev.Respir.Dis，1978）制备卷烟烟雾提取物（CSE）。人类胎儿肺成纤维细胞（HFL-1）暴露于不同浓度的CSE中并持续不同的持续时间。使用ELISA测量VEGF释放到培养基中。使用Smad3和TGF-beta1受体（TbetaR1）siRNA，还研究了TGF-beta1 / Smad3作为潜在效应的途径。结果：HSE-1以浓度和时间依赖性方式诱导CSE诱导的VEGF释放。 CSE诱导HFL-1细胞中Smad3磷酸化和核易位。 siRNA沉默Smad3不仅消除了CSE对VEGF释放的刺激作用，而且抑制了基线VEGF的产生。通过药理抑制剂（SB431542）抑制TbetaR1可以显着降低HFL-1响应CSE的VEGF释放，而TbetaR1 siRNA证实了这一作用。相反，尼古丁以剂量和时间依赖性方式抑制HFL-1释放的VEGF。结论：我们的发现表明CSE刺激肺成纤维细胞释放VEGF，而Smad3介导刺激VEGF释放。尼古丁不能解释人肺成纤维细胞中CSE对VEGF产生的刺激作用。肺成纤维细胞产生VEGF的能力可能在呼吸系统疾病的发病机理中起作用。

著录项

  • 作者

    Farid, Maha.;

  • 作者单位

    University of Nebraska Medical Center.;

  • 授予单位 University of Nebraska Medical Center.;
  • 学科 Health Sciences Toxicology.;Health Sciences Public Health.;Health Sciences Medicine and Surgery.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 88 p.
  • 总页数 88
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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