EphA2 receptor mediates increased vascular permeability in lung injury due to viral infection and hypoxia
EphA2 receptor mediates increased vascular permeability in lung injury due to viral infection and hypoxia
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DOI：
10.1152/ajplung.00118.2009
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发表时间：
2009-11-01
影响因子：
4.9
通讯作者：
Carpenter, Todd C.
中科院分区：
文献类型：
--
作者：
Cercone, Melissa A.;Schroeder, William;Carpenter, Todd C.
Cecone MA、Schroeder W、Schomberg S、Carpenter TC。 EphA2 受体介导病毒感染和缺氧导致的肺损伤中血管通透性增加。 Am J Physiol Lung Cell Mol Physiol 297: L856-L863, 2009。首次发表于 2009 年 8 月 14 日； doi: 10.1152/ajplung.00118.2009.-Ephrin 家族受体酪氨酸激酶是血管生成的介质，也可能调节肺内皮屏障功能。先前的研究表明，EphA 肝配蛋白受体的刺激会导致完整肺中的血管渗漏增加以及培养的内皮细胞的通透性增加。 EphA 受体是否参与与肺损伤相关的通透性变化尚不清楚。我们在暴露于病毒性呼吸道感染并暴露于中度缺氧（先前描述的肺损伤模型）的年轻大鼠中研究了这个问题。我们发现EphA2受体在正常肺中表达，并且与正常对照动物相比，缺氧感染(HV)大鼠的肺中EphA2表达显着上调。免疫组织化学显示 EphA2 表达增加主要在水肿的肺泡间隔区域。在 HV 大鼠中，EphA2 与可溶性诱饵受体 EphA2/Fc 或单克隆抗 EphA2 抗体的拮抗作用减少了白蛋白外渗和水肿形成的组织学证据 (P < 0.01)。 HV 大鼠的血管渗漏在很大程度上是由肺内皮素 (ET) 水平升高介导的。在 HV 大鼠中，波生坦对 ET 受体的拮抗作用导致 EphA2 mRNA 和蛋白表达降低（P < 0.01）。对培养的大鼠肺微血管内皮细胞进行的实验表明，ET 可增加内皮 EphA2 的表达。这些结果表明，EphA2 表达在肺损伤中增加，导致受伤肺中的血管渗漏，并且在内皮细胞中受到 ET 的调节。 EphA2 可能是以前未被认识到的肺损伤病理生理学的一个贡献者。
Cercone MA, Schroeder W, Schomberg S, Carpenter TC. EphA2 receptor mediates increased vascular permeability in lung injury due to viral infection and hypoxia. Am J Physiol Lung Cell Mol Physiol 297: L856-L863, 2009. First published August 14, 2009; doi: 10.1152/ajplung.00118.2009.-Ephrin family receptor tyrosine kinases are mediators of angiogenesis that may also regulate endothelial barrier function in the lung. Previous work has demonstrated that stimulation of EphA ephrin receptors causes increased vascular leak in the intact lung and increased permeability in cultured endothelial cells. Whether EphA receptors are involved in the permeability changes associated with lung injury is unknown. We studied this question in young rats exposed to viral respiratory infection combined with exposure to moderate hypoxia, a previously described lung injury model. We found that the EphA2 receptor is expressed in normal lung and that EphA2 expression is markedly upregulated in the lungs of hypoxic infected (HV) rats compared with normal control animals. Immunohistochemistry showed increased EphA2 expression principally in areas of edematous alveolar septae. In HV rats, EphA2 antagonism with either the soluble decoy receptor EphA2/Fc or with monoclonal anti-EphA2 antibody reduced albumin extravasation and histological evidence of edema formation (P < 0.01). Vascular leak in HV rats is mediated in large part by increased lung endothelin (ET) levels. In HV rats, ET receptor antagonism with bosentan resulted in reduced EphA2 mRNA and protein expression (P < 0.01). Experiments with cultured rat lung microvascular endothelial cells demonstrated that ET increases endothelial EphA2 expression. These results suggest that EphA2 expression is increased in lung injury, contributes to vascular leak in the injured lung, and is regulated in endothelial cells by ET. EphA2 may be a previously unrecognized contributor to the pathophysiology of lung injury.