Mast cells can mediate vascular permeability through regulation of the PI3K-HIF-1α-VEGF axis
Mast cells can mediate vascular permeability through regulation of the PI3K-HIF-1α-VEGF axis
复制标题
DOI：
10.1164/rccm.200801-008oc
复制
发表时间：
2008-10-15
影响因子：
24.7
通讯作者：
Lee, Yong Chul
中科院分区：
文献类型：
--
作者：
Lee, Kyung Sun;Kim, So Ri;Lee, Yong Chul
理由：支气管炎症通常伴有血管通透性增加。肥大细胞释放许多直接作用于脉管系统的介质，导致血管舒张、通透性增加和随后的血浆蛋白外渗。血管内皮生长因子（VEGF）通过其对血管通透性的影响而参与哮喘组织水肿。然而，肥大细胞在变应性气道疾病中vegf介导的信号传导中的作用尚不清楚。目的：本研究旨在探讨肥大细胞在变应性气道疾病中vegf介导的信号转导中的作用。方法：采用遗传肥大细胞缺陷型WBB6F(1)-Kit(W)/Kit(W-v) （W/W-v）小鼠和基因正常型WBB6F(1)（+/+）小鼠变应性气道疾病模型，研究肥大细胞在变应性气道疾病中vegf介导的信号转导中的作用，更具体地说，是在血管通透性方面的作用。本研究以卵清蛋白（OVA）致敏的无佐剂小鼠和OVA致敏小鼠为研究对象，揭示了过敏性气道疾病的以下典型病理生理特征：气道炎症细胞增加，气道高反应性，血管通透性增加，VEGF水平升高。然而，吸入OVA后W/W-v小鼠的VEGF和血浆渗出水平明显低于WBB6F(1)（+/+）小鼠。此外，肥大细胞重建的W/W-v小鼠恢复血管通透性和VEGF水平与WBB6F(1)（+/+）小鼠相似。我们的数据还显示，在变应性气道疾病中，缺氧诱导因子-1 α (HIF-1 α)通过磷脂酰肌醇3-激酶(PI3K)-HIF-1 α途径激活，调节VEGF的表达。结论：肥大细胞通过调节PI3K-HIF-1 α - vegf轴调节血管通透性。
Rationale: Bronchial inflammation is usually accompanied by increased vascular permeability. Mast cells release a number of mediators that act directly on the vasculature, resulting in vasodilatation, increased permeability, and subsequent plasma protein extravasation. Vascular endothelial growth factor (VEGF) has been implicated to contribute to asthmatic tissue edema through its effect on vascular permeability. However, the effects of mast cells on VEGF-mediated signaling in allergic airway disease are not clearly understood.Objectives: An aim of the present study was to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease.Methods: We used genetically mast cell-deficient WBB6F(1)-Kit(W)/Kit(W-v) (W/W-v) mice and the congenic normal WBB6F(1)(+/+) mouse model for allergic airway disease to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease, more specifically in vascular permeability.Measurements and Main Results: Our present study, with ovalbumin (OVA)-sensitized without adjuvant and OVA-challenged mice, revealed the following typical pathophysiologic features of allergic airway diseases: increased inflammatory cells of the airways, airway hyper-responsiveness, increased vascular permeability, and increased levels of VEGF. However, levels of VEGF and plasma exudation in W/W-v mice after OVA inhalation were significantly lower than levels in WBB6F(1)(+/+) mice. Moreover, mast cell-reconstituted W/W-v mice restored vascular permeability and VEGF levels similar to those of the WBB6F(1)(+/+) mice. Our data also showed that VEGF expression was regulated by hypoxia-inducible factor-1 alpha (HIF-1 alpha) activation through the phosphatidylinositol 3-kinase (PI3K)-HIF-1 alpha pathway in allergic airway disease.Conclusions: These results suggest that mast cells modulate vascular permeability by the regulation of the PI3K-HIF-1 alpha-VEGF axis.