Intercellular adhesion molecule-1-dependent neutrophil adhesion to endothelial cells induces caveolae-mediated pulmonary vascular hyperpermeability
Intercellular adhesion molecule-1-dependent neutrophil adhesion to endothelial cells induces caveolae-mediated pulmonary vascular hyperpermeability
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DOI：
10.1161/circresaha.107.167486
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发表时间：
2008-06-20
影响因子：
20.1
通讯作者：
Minshall, Richard D.
中科院分区：
文献类型：
--
作者：
Hu, Guochang;Vogel, Stephen M.;Minshall, Richard D.
我们研究了小窝在多形核中性粒细胞（PMN）激活引起的肺血管通透性增加和水肿形成机制中的作用。我们观察到中性粒细胞激活引起的肺血管通透性增加需要caveolae支架蛋白caveolin-1。在 Caveolin-1 敲除小鼠中，PMN 激活诱导的通透性增加被阻断，而在大鼠中，通过抑制 Caveolin-1 表达，则阻断了由 PMN 激活引起的通透性增加。该反应还依赖于 Caveolin-1 的 Src 磷酸化，已知该磷酸化可激活内皮细胞中小凹介导的内吞作用。为了解决 PMN 与内皮细胞相互作用的作用，我们使用了细胞间粘附分子 (ICAM)-1 阻断单克隆抗体。阻止 ICAM-1 介导的 PMN 与内皮细胞结合可消除 Caveolin-1 的 Src 磷酸化以及内皮通透性的增加。通过交联直接激活 ICAM-1 重现了这些反应，表明 ICAM-1 激活了导致小凹介导的内皮通透性过高的 Caveolin-1 信号传导。我们的结果为以下新概念提供了支持：由粘附于血管壁的 PMN 激活引起的肺血管通透性过高的很大一部分依赖于小凹蛋白-1 的信号传导和增加的小凹介导的转胞吞作用。因此，在制定针对中性粒细胞介导的炎症性疾病（如急性肺损伤）的治疗干预措施时，考虑跨内皮囊泡通透性通路在水肿形成中的作用非常重要。
We investigated the role of caveolae in the mechanism of increased pulmonary vascular permeability and edema formation induced by the activation of polymorphonuclear neutrophils (PMNs). We observed that the increase in lung vascular permeability induced by the activation of PMNs required caveolin-1, the caveolae scaffold protein. The permeability increase induced by PMN activation was blocked in caveolin-1 knockout mice and by suppressing caveolin-1 expression in rats. The response was also dependent on Src phosphorylation of caveolin-1 known to activate caveolae-mediated endocytosis in endothelial cells. To address the role of PMN interaction with endothelial cells, we used an intercellular adhesion molecule (ICAM)-1 blocking monoclonal antibody. Preventing the ICAM-1-mediated PMN binding to endothelial cells abrogated Src phosphorylation of caveolin-1, as well as the increase in endothelial permeability. Direct ICAM-1 activation by crosslinking recapitulated these responses, suggesting that ICAM-1 activates caveolin-1 signaling responsible for caveolae-mediated endothelial hyperpermeability. Our results provide support for the novel concept that a large component of pulmonary vascular hyperpermeability induced by activation of PMNs adherent to the vessel wall is dependent on signaling via caveolin-1 and increased caveolae-mediated transcytosis. Thus, it is important to consider the role of the transendothelial vesicular permeability pathway that contributes to edema formation in developing therapeutic interventions against PMN-mediated inflammatory diseases such as acute lung injury.