The vitronectin-binding function of PAI-1 exacerbates lung fibrosis in mice
The vitronectin-binding function of PAI-1 exacerbates lung fibrosis in mice
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DOI：
10.1182/blood-2010-12-324574
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发表时间：
2011-08-25
期刊：
影响因子：
20.3
通讯作者：
Sisson, Thomas H.
中科院分区：
文献类型：
--
作者：
Courey, Anthony J.;Horowitz, Jeffrey C.;Sisson, Thomas H.
纤溶酶原激活物抑制剂-1 （PAI-1）在肺纤维化患者的肺中升高，动物研究表明，PAI-1水平的实验操作直接影响肺损伤后瘢痕形成的程度。PAI-1有两种已知的特性可以增强纤维化，即抑制纤溶酶生成的抗蛋白酶活性，以及干扰细胞粘附到这种细胞外基质蛋白的体外连接蛋白结合功能。为了确定每个PAI-1功能在肺纤维化中的相对重要性，我们将具有完整抗蛋白酶或体外连接蛋白结合活性的突变PAI-1蛋白给予博莱霉素损伤的PAI-1基因缺陷小鼠。我们发现PAI-1的体外连接蛋白结合能力是其加剧气管内博莱霉素诱导的肺瘢痕形成能力的主要决定因素。通过基因修饰表达PAI-1突变蛋白的小鼠，在博莱霉素模型中证实了PAI-1的vitronectin结合功能在纤维化中的关键作用。我们得出结论，PAI-1的体外连接蛋白结合功能在其加剧肺纤维化过程的能力中是必要和充分的。[血液。2011;118(8):2313-2321]
Plasminogen activator inhibitor-1 (PAI-1) is increased in the lungs of patients with pulmonary fibrosis, and animal studies have shown that experimental manipulations of PAI-1 levels directly influence the extent of scarring that follows lung injury. PAI-1 has 2 known properties that could potentiate fibrosis, namely an antiprotease activity that inhibits the generation of plasmin, and a vitronectin-binding function that interferes with cell adhesion to this extracellular matrix protein. To determine the relative importance of each PAI-1 function in lung fibrogenesis, we administered mutant PAI-1 proteins that possessed either intact antiprotease or vitronectin-binding activity to bleomycin-injured mice genetically deficient in PAI-1. We found that the vitronectin-binding capacity of PAI-1 was the primary determinant required for its ability to exacerbate lung scarring induced by intratracheal bleomycin administration. The critical role of the vitronectin-binding function of PAI-1 in fibrosis was confirmed in the bleomycin model using mice genetically modified to express the mutant PAI-1 proteins. We conclude that the vitronectin-binding function of PAI-1 is necessary and sufficient in its ability to exacerbate fibrotic processes in the lung. (Blood. 2011; 118(8): 2313-2321)