Recombinant IGFBP-3 inhibits allergic lung inflammation, VEGF production, and vascular leak in a mouse model of asthma
Recombinant IGFBP-3 inhibits allergic lung inflammation, VEGF production, and vascular leak in a mouse model of asthma
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DOI：
10.1111/j.1398-9995.2012.02837.x
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发表时间：
2012-07-01
期刊：
影响因子：
12.4
通讯作者：
Lee, Y. C.
中科院分区：
文献类型：
--
作者：
Kim, S. R.;Lee, K. S.;Lee, Y. C.
背景血管内皮生长因子（VEGF）在支气管哮喘中起促炎介质和血管通透性因子的作用。胰岛素样生长因子（IGF）-I也参与与支气管哮喘相关的炎症过程，并刺激VEGF表达。IGF结合蛋白（IGFBPs），特别是IGFBP-3，具有独特的特性，可以干扰各种生物过程。方法采用卵清蛋白（OVA）诱导的小鼠过敏性气道疾病模型，研究外源性IGFBP-3对过敏原诱导的支气管炎症和气道高反应性的预防和治疗作用，特别是对VEGF表达的调节。结果给予OVA吸入小鼠重组人IGFBP-3显著减弱了肺中缺氧诱导因子（HIF）-a活性、IGF-I产生和VEGF蛋白水平的增加。此外，阻断IGF-I的作用降低了OVA诱导的VEGF表达、气道炎症和支气管高反应性。施用重组人IGFBP-3或CBO-P11还显著降低了OVA吸入小鼠肺中炎性细胞、气道高反应性、IL-4、IL-5、IL-13水平和血管通透性的增加。此外，当在完成OVA吸入后施用重组人IGFBP-3时，也观察到IGFBP-3的这些治疗效果。结论外源性IGFBP-3可能通过调节HIF-1a/HIF-2a信号通路介导的血管渗漏和VEGF表达，以及IGF-I的作用，减轻小鼠过敏性气道疾病中抗原诱导的气道炎症和高反应性。
Background Vascular endothelial growth factor (VEGF) plays a pro-inflammatory mediator as well as a vascular permeability factor in bronchial asthma. Insulin-like growth factor (IGF)-I is also involved in the inflammatory process associated with bronchial asthma and stimulates VEGF expression. The IGF-binding proteins (IGFBPs), especially IGFBP-3, display distinctive properties and can interfere with various biological processes. Methods In this study, an ovalbumin (OVA)-induced murine model of allergic airway disease was used to investigate which mechanism is implicated in the preventive and therapeutic actions of IGFBP-3 administered exogenously on allergen-induced bronchial inflammation and airway hyper-responsiveness, in particular focusing on the regulation of VEGF expression. Results Administration of recombinant human IGFBP-3 to OVA-inhaled mice substantially attenuated the increases in hypoxia-inducible factor (HIF)-a activity, IGF-I production, and VEGF protein levels in the lung. In addition, the blockade of IGF-I action decreased the OVA-induced VEGF expression, airway inflammation, and bronchial hyper-responsiveness. The administration of recombinant human IGFBP-3 or CBO-P11 also reduced significantly increases in inflammatory cells, airway hyper-responsiveness, levels of IL-4, IL-5, IL-13, and vascular permeability in the lung of OVA-inhaled mice. Moreover, when recombinant human IGFBP-3 was administered after the completion of OVA inhalation, these therapeutic effects of IGFBP-3 were also observed. Conclusions These results indicate that IGFBP-3 administered exogenously may attenuate antigen-induced airway inflammation and hyper-responsiveness through the modulation of vascular leakage and VEGF expression mediated by HIF-1a/HIF-2a signaling as well as IGF-I action in allergic airway disease of mice.