Department of Pharmacology and Physiology, University of Rochester, New York 14642, USA.
Am J Physiol Cell Physiol. 2011 Oct;301(4):C804-13. doi: 10.1152/ajpcell.00135.2011. Epub 2011 Jun 8.
Activated neutrophils interacting with the vessel wall can alter vascular permeability to macromolecules such as albumin via release of various secretion products that induce changes in the endothelial monolayer. In the current work we used cremaster microvessels of anesthetized mice to show that, in addition to this paracrine mechanism, leukocyte ligation of endothelial ICAM-1 directly activates endothelial cell (EC) signaling, altering EC permeability to albumin [i.e., solute permeability (P(s))]. We show that antibody cross-linking of surface ICAM-1 in intact microvessels is sufficient to increase P(s) even in the absence of interacting leukocytes. Unstimulated arterioles do not support leukocyte-EC interactions, but despite this, antibody ligation of ICAM-1 in these vessels induced a twofold increase in P(s). Similarly, in venules that were depleted of interacting neutrophils, P(s) was decreased to below resting levels and was restored by ligation of ICAM-1. Use of function-blocking antibodies to separately block leukocyte rolling or adhesion under unstimulated or TNF-α-activated conditions established that both rolling and adhered leukocytes contribute to P(s) regulation in situ. Both rolling and adhesion activated EC-dependent signaling mechanisms that increased P(s). ICAM-1 ligation with primary antibody alone or primary followed by secondary antibodies showed that regulation of P(s) is directly dependent on the degree of ICAM-1 clustering. Under physiological versus inflamed conditions, respectively, this ICAM-1 clustering-dependent regulation of P(s) switches from PKC dependent and Src independent to Src dependent and PKC independent. This study thus identifies a new mechanism by which antiadhesion treatment may constitute a potential therapy for tissue edema.
活化的中性粒细胞与血管壁相互作用可通过释放各种诱导内皮单层改变的分泌产物来改变白蛋白等大分子物质的血管通透性。在目前的工作中，我们使用麻醉小鼠的提睾肌微血管来表明，除了这种旁分泌机制外，白细胞与内皮细胞 ICAM-1 的连接可直接激活内皮细胞 (EC) 信号，改变 EC 对白蛋白的通透性[即溶质通透性 (P(s))]。我们表明，在完整的微血管中，表面 ICAM-1 的抗体交联足以增加 P(s)，即使没有相互作用的白细胞也是如此。未受刺激的小动脉不支持白细胞-EC 相互作用，但尽管如此，这些血管中 ICAM-1 的抗体交联仍会导致 P(s)增加两倍。同样，在没有相互作用的中性粒细胞的静脉中，P(s)降低至静息水平以下，并且通过 ICAM-1 的交联可以恢复。在未受刺激或 TNF-α 激活条件下，使用功能阻断抗体分别阻断白细胞滚动或粘附，证实滚动和粘附的白细胞都有助于原位 P(s)调节。滚动和粘附均激活了依赖 EC 的信号机制，从而增加了 P(s)。用原抗体单独或原抗体后再用二抗交联 ICAM-1 表明，P(s)的调节直接取决于 ICAM-1 聚集的程度。在生理和炎症条件下，分别为 PKC 依赖和 Src 独立，到 Src 依赖和 PKC 独立。因此，这项研究确定了一种新的机制，通过这种机制，抗粘附治疗可能成为治疗组织水肿的潜在疗法。
