Levin E G, Santell L, Osborn K G
Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037, USA.
J Cell Sci. 1997 Jan;110 ( Pt 2):139-48. doi: 10.1242/jcs.110.2.139.
Plasma tissue plasminogen activator (tPA) has long been considered to be the product of the endothelial cells that line the various parts of the vascular system regardless of vessel size or location. To determine whether this was truly the case in vivo, the distribution of tPA in the endothelium of the mouse lung and other tissues was evaluated. Immunohistochemical analysis of normal lung tissue showed positive staining limited to the endothelial cells of the bronchial arteries regardless of size with few cells of the pulmonary circulation associated with tPA. The pulmonary vessels that did contain endothelial cell-derived tPA were consistently between 7 and 30 microns in diameter. No capillary or large vessel pulmonary endothelium ever stained positive. These results were also observed in primate lung tissue where the bronchial endothelium of all vessels, even down to capillary size, contained tPA while none of the pulmonary endothelium did. Prolonged exposure of mice to hyperoxic conditions promotes acute lung injury and associated inflammation. Using this model, the effect of inflammation on endothelial cell tPA expression was evaluated. A 4.5-fold increase in the number of pulmonary vessels staining positive for tPA was observed after 66 hours with all of these vessels having a diameter between 7 and 30 microns. Again, none of the endothelium of large arteries or veins nor the capillaries had tPA. Whole tissue tPA mRNA increased dramatically with hyperoxia and in situ hybridization analysis showed tPA mRNA in the endothelium of the same types of vessels as antigen. The tPA localized to both the bronchial and pulmonary endothelium was active with neither tPA-PAI-1 complexes nor urokinase found in perfused lung tissue. These results indicate that endothelial cell tPA expression, either constitutive or induced by a pathologic event, is a function of a highly select group of endothelial cells which are defined by their association with vessels of discrete size and/or anatomic location. Thus, the widely held concept that the steady state level of plasma tPA is maintained through its constitutive production by all endothelial cells of the vascular system is invalid. Also suggested is the possibility that endothelial cell tPA might play a broader role than simply maintaining vessel patency as a component of the fibrinolytic pathway and contribute to complex dynamic processes such as inflammation.
血浆组织型纤溶酶原激活剂（tPA）长期以来一直被认为是血管系统各部位内衬内皮细胞的产物，无论血管大小或位置如何。为了确定体内情况是否确实如此，对小鼠肺和其他组织内皮中的tPA分布进行了评估。正常肺组织的免疫组织化学分析显示，阳性染色仅限于支气管动脉的内皮细胞，无论大小如何，肺循环中只有少数细胞与tPA相关。确实含有内皮细胞源性tPA的肺血管直径始终在7至30微米之间。没有毛细血管或大血管的肺内皮呈阳性染色。在灵长类动物肺组织中也观察到了这些结果，其中所有血管的支气管内皮，甚至小至毛细血管大小，都含有tPA，而肺内皮均无。将小鼠长时间暴露于高氧环境会促进急性肺损伤和相关炎症。利用这个模型，评估了炎症对内皮细胞tPA表达的影响。66小时后，观察到tPA染色阳性的肺血管数量增加了4.5倍，所有这些血管的直径都在7至30微米之间。同样，大动脉或静脉以及毛细血管的内皮均无tPA。全组织tPA mRNA随着高氧而显著增加，原位杂交分析显示tPA mRNA存在于与抗原相同类型血管的内皮中。定位于支气管和肺内皮的tPA具有活性，在灌注肺组织中未发现tPA-PAI-1复合物或尿激酶。这些结果表明，内皮细胞tPA表达，无论是组成性的还是由病理事件诱导的，都是一组高度选择性内皮细胞的功能，这些内皮细胞由它们与特定大小和/或解剖位置的血管的关联来定义。因此，普遍认为血浆tPA的稳态水平是通过血管系统所有内皮细胞的组成性产生来维持的这一概念是无效的。还提示内皮细胞tPA可能发挥比单纯作为纤维蛋白溶解途径的一个组成部分维持血管通畅更广泛的作用，并有助于诸如炎症等复杂的动态过程。
