Waltz D A, Fujita R M, Yang X, Natkin L, Zhuo S, Gerard C J, Rosenberg S, Chapman H A
Department of Medicine, Children's Hospital, Boston, Massachusetts 02115, USA.
Am J Respir Cell Mol Biol. 2000 Mar;22(3):316-22. doi: 10.1165/ajrcmb.22.3.3713.
The urokinase receptor (uPAR) binds and localizes urokinase activity at cellular surfaces, facilitating fibrinolysis and cellular migration at sites of tissue injury. uPAR also participates in cellular signaling and regulates integrin-dependent adhesion and migration in vitro. We now report evidence that uPAR occupancy regulates cellular migration in vivo in the absence of functional urokinase. Recombinant murine KC (1.5 microg), a potent neutrophil chemoattractant, was delivered to the lungs of wild-type, urokinase-deficient or uPAR-deficient mice 18 h after intraperitoneal injection of 200 microg human immunoglobulin G (IgG) or a fusion protein composed of an amino-terminal receptor-binding fragment of urokinase and a human IgG Fc fragment (GFD-Fc). Whole lung lavage for recovery of leukocytes was performed 4 h later. KC treatment resulted in a 100-fold increase in lavage neutrophils. GFD-Fc injection resulted in >50% reduction in neutrophil influx in both wild-type and urokinase-deficient animals but had no effect on uPAR -/- mice. A concomitant reduction in alveolar protein leakage but no change in numbers of circulating neutrophils accompanied this attenuated inflammatory response. The reduction in neutrophil influx induced by GFD-Fc is thus related to uPAR occupancy and yet not due to disruption of uPAR-mediated proteolysis. These observations verify that protease-independent functions of uPAR operate in vivo and identify uPAR as a potential target for regulation of inflammatory processes characterized by neutrophil-mediated injury.
尿激酶受体（uPAR）可结合尿激酶并将其活性定位在细胞表面，促进组织损伤部位的纤维蛋白溶解和细胞迁移。uPAR还参与细胞信号传导，并在体外调节整合素依赖性黏附和迁移。我们现在报告证据表明，在缺乏功能性尿激酶的情况下，uPAR的占据可调节体内细胞迁移。在腹腔注射200μg人免疫球蛋白G（IgG）或由尿激酶的氨基末端受体结合片段和人IgG Fc片段组成的融合蛋白（GFD-Fc）18小时后，将重组鼠KC（1.5μg），一种有效的中性粒细胞趋化因子，注入野生型、尿激酶缺陷型或uPAR缺陷型小鼠的肺部。4小时后进行全肺灌洗以回收白细胞。KC治疗导致灌洗中性粒细胞增加100倍。GFD-Fc注射导致野生型和尿激酶缺陷型动物的中性粒细胞流入减少>50%，但对uPAR -/-小鼠没有影响。这种减弱的炎症反应伴随着肺泡蛋白渗漏的同时减少，但循环中性粒细胞数量没有变化。因此，GFD-Fc诱导的中性粒细胞流入减少与uPAR的占据有关，但不是由于uPAR介导的蛋白水解的破坏。这些观察结果证实了uPAR的蛋白酶非依赖性功能在体内起作用，并确定uPAR是调节以中性粒细胞介导的损伤为特征的炎症过程的潜在靶点。
