Hattori N, Sisson T H, Xu Y, Desai T J, Simon R H
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-0642, USA.
Am J Physiol. 1999 Sep;277(3):L573-9. doi: 10.1152/ajplung.1999.277.3.L573.
In vitro studies have demonstrated that the binding of urokinase-type plasminogen activator (uPA) to its cell surface receptor (uPAR) greatly accelerates plasminogen activation. However, the role of uPAR in clearing abnormal fibrin deposits from the lung is uncertain. Knowing that uPA binding to uPAR is species specific, we used adenoviral vectors to transfer human or murine uPA genes into human or mouse epithelial cells in vitro and to mouse lungs in vivo. By measuring degradation of fluorescein-labeled fibrin, we found that uPA lysed fibrin matrices more efficiently when expressed in cells of the same species. A monoclonal antibody that blocks the binding of human uPA to human uPAR suppressed fibrin degradation by human cells expressing human uPA but not murine uPA. Importantly, 3 days after intratracheal delivery of the vectors, mice receiving murine uPA transgenes degraded fibrin matrices formed within their air spaces more efficiently than animals transduced with human uPA genes. These results show that uPA bound to uPAR increases the efficiency of fibrinolysis on epithelial cell surfaces in a biologically relevant fashion.
体外研究表明，尿激酶型纤溶酶原激活剂（uPA）与其细胞表面受体（uPAR）的结合能极大地加速纤溶酶原的激活。然而，uPAR在清除肺部异常纤维蛋白沉积中的作用尚不确定。鉴于uPA与uPAR的结合具有物种特异性，我们使用腺病毒载体在体外将人或鼠uPA基因导入人或小鼠上皮细胞，并在体内导入小鼠肺部。通过测量荧光素标记纤维蛋白的降解情况，我们发现当uPA在同一物种的细胞中表达时，其溶解纤维蛋白基质的效率更高。一种能阻断人uPA与人uPAR结合的单克隆抗体抑制了表达人uPA的人细胞对纤维蛋白的降解，但对表达鼠uPA的细胞无效。重要的是，在气管内递送载体3天后，接受鼠uPA转基因的小鼠比转导人uPA基因的动物更有效地降解了其气腔内形成的纤维蛋白基质。这些结果表明，与uPAR结合的uPA以生物学相关的方式提高了上皮细胞表面纤维蛋白溶解的效率。
