Suzuki Masaru, Betsuyaku Tomoko, Nagai Katsura, Fuke Satoshi, Nasuhara Yasuyuki, Kaga Kichizo, Kondo Satoshi, Hamamura Ichiro, Hata Junko, Takahashi Hiroshi, Nishimura Masaharu
First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Inhal Toxicol. 2008 Feb;20(3):349-59. doi: 10.1080/08958370701866412.
Vascular endothelial growth factor (VEGF) signaling is crucial for lung structure maintenance. Although VEGF deficiency plays a role in the pathogenesis of emphysema in animals, little is known about VEGF expression levels and functions, as well as VEGF receptors, in airway epithelial cells, which are in direct contact with the environment. In this study, C57BL/6J mice were exposed to cigarette smoke (CS) for short (approximately 10 days) and long (4-24 wk) time periods, and bronchiolar expressions of VEGF and its receptors VEGFR-1 and VEGFR-2 were examined. The relationships between the expressions of VEGF, VEGFR-1, and VEGFR-2 and smoking histories and/or chronic obstructive pulmonary disease (COPD) were examined in humans. The mRNA levels were quantified in bronchiolar epithelium harvested by laser capture microdissection in both mouse and human lung tissues or in human bronchial epithelium harvested by bronchoscopic brushing. The VEGF protein level was assessed by immunohistochemistry or enzyme-linked immunosorbent assay. Repeated CS exposure downregulated bronchiolar expressions of VEGF and both VEGF receptors at various time points prior to the development of emphysema. In humans, bronchiolar VEGF was significantly decreased in smokers with COPD compared to lifelong nonsmokers, as well as to smokers without COPD; however, there was no difference in bronchiolar VEGF levels between lifelong nonsmokers and smokers without COPD. On the other hand, bronchiolar VEGFR-2 was downregulated in smokers with and without COPD compared to lifelong nonsmokers. These findings suggest the association of downregulation of bronchiolar VEGF and its receptors with cigarette smoking and COPD.
血管内皮生长因子（VEGF）信号传导对于维持肺结构至关重要。尽管VEGF缺乏在动物肺气肿发病机制中起作用，但对于与环境直接接触的气道上皮细胞中的VEGF表达水平和功能以及VEGF受体，人们了解甚少。在本研究中，将C57BL/6J小鼠短期（约10天）和长期（4 - 24周）暴露于香烟烟雾（CS）中，并检测细支气管中VEGF及其受体VEGFR - 1和VEGFR - 2的表达。在人类中研究了VEGF、VEGFR - 1和VEGFR - 2的表达与吸烟史和/或慢性阻塞性肺疾病（COPD）之间的关系。通过激光捕获显微切割从小鼠和人肺组织中获取的细支气管上皮或通过支气管镜刷检获取的人支气管上皮中定量mRNA水平。通过免疫组织化学或酶联免疫吸附测定评估VEGF蛋白水平。在肺气肿发生前的各个时间点，反复暴露于CS会下调细支气管中VEGF和两种VEGF受体的表达。在人类中，与终身不吸烟者以及无COPD的吸烟者相比，患有COPD的吸烟者细支气管VEGF显著降低；然而，终身不吸烟者和无COPD的吸烟者之间细支气管VEGF水平没有差异。另一方面，与终身不吸烟者相比，患有和未患有COPD的吸烟者细支气管VEGFR - 2均下调。这些发现表明细支气管VEGF及其受体的下调与吸烟和COPD有关。
