Integrin αvβ5 regulates lung vascular permeability and pulmonary endothelial barrier function
Integrin αvβ5 regulates lung vascular permeability and pulmonary endothelial barrier function
复制标题
DOI：
10.1165/rcmb.2006-0238oc
复制
发表时间：
2007-03-01
影响因子：
6.4
通讯作者：
Pittet, Jean-Francois
中科院分区：
文献类型：
--
作者：
Su, George;Hodnett, Maki;Pittet, Jean-Francois
肺血管通透性增加是导致急性肺损伤(ALI)呼吸衰竭的重要因素。我们发现，在两种不同的ALI模型中，针对整合素αvβ5的功能阻断抗体可以阻止肺血管通透性的发展：大鼠缺血再灌注(由血管内皮生长因子[VEGF]介导)和小鼠呼吸机诱导的肺损伤(VILI)(至少部分由转化生长因子-β(TGF-β)介导)。整合素β5亚单位突变为零的纯合子小鼠也受到保护，使其免受肺内皮细胞肺血管通透性的影响，基因缺失和阻断αvβ5均可防止由血管内皮生长因子、转化生长因子-β和凝血酶诱导的单层通透性增加。此外，这些激动剂诱导的肌动蛋白应激纤维的形成通过阻断αvβ5而减弱，这表明αvβ5通过促进与肌动蛋白细胞骨架的相互作用来调节诱导的肺内皮细胞通透性。这些结果证实整合素αvβ5是肺血管通透性增加的中枢调节因子，是ALI潜在的有吸引力的治疗靶点。
Increased lung vascular permeability is an important contributor to respiratory failure in acute lung injury (ALI). We found that a function-blocking antibody against the integrin alpha v beta 5 prevented development of lung vascular permeability in two different models of ALI: ischemia-reperfusion in rats (mediated by vascular endothelial growth factor [VEGF]) and ventilation-induced lung injury (VILI) in mice (mediated, at least in part, by transforming growth factor-beta (TGF-beta). Knockout mice homozygous for a null mutation of the integrin beta 5 subunit were also protected from lung vascular permeability in VILL In pulmonary endothelial cells, both the genetic absence and blocking of alpha v beta 5 prevented increases in monolayer permeability induced by VEGF, TGF-beta, and thrombin. Furthermore, actin stress fiber formation induced by each of these agonists was attenuated by blocking alpha v beta 5, suggesting that alpha v beta 5 regulates induced pulmonary endothelial permeability by facilitating interactions with the actin cytoskeleton. These results identify integrin alpha v beta 5 as a central regulator of increased pulmonary vascular permeability and a potentially attractive therapeutic target in ALI.