Tuan T L, Zhu J Y, Sun B, Nichter L S, Nimni M E, Laug W E
Department of Surgery, Childrens Hospital Los Angeles, University of Southern California, School of Medicine, USA.
J Invest Dermatol. 1996 May;106(5):1007-11. doi: 10.1111/1523-1747.ep12338552.
Using a 3-dimensional fibrin gel model system simulating fibroplasia of wound repair, we investigated the interaction between keloid fibroblasts and fibrin matrix and compared it with that of normal fibroblasts. Normal skin fibroblasts caused fibrin gel degradation under serum-free conditions, whereas keloid fibroblasts did not cause microscopically detectable gel degradation. Fibrin gel degradation occurred through plasmin-mediated fibrinolysis, which was initiated by fibroblasts exhibited high uPA but low plasminogen activator inhibitor-1 (PAI-1) activities, and transforming growth factor-beta 1 prevented fibrinolysis of normal fibroblasts by upregulating PAI-1 while downregulating uPA activities. In contrast, keloid fibroblasts exhibited an intrinsically high level of PAI-1 and a low level of uPA. This change in the ratio of activator and inhibitor activities was attributed to altered fibrin degradation by keloid fibroblasts. The PAI-1 increase was also demonstrated at the RNA level by Northern analysis. In terms of the pivotal role of the plasmin/plasminogen activator system in matrix remodeling, the elevated PAI-1 level exhibited by keloid fibroblasts may have significant consequences not only in altered fibrin degradation, but also in subsequent repair steps that lead to keloids and fibrosis.
利用模拟伤口修复纤维增生的三维纤维蛋白凝胶模型系统，我们研究了瘢痕疙瘩成纤维细胞与纤维蛋白基质之间的相互作用，并将其与正常成纤维细胞的相互作用进行了比较。正常皮肤成纤维细胞在无血清条件下可导致纤维蛋白凝胶降解，而瘢痕疙瘩成纤维细胞在显微镜下未引起可检测到的凝胶降解。纤维蛋白凝胶降解是通过纤溶酶介导的纤维蛋白溶解发生的，这种溶解由具有高尿激酶型纤溶酶原激活物（uPA）但低纤溶酶原激活物抑制剂-1（PAI-1）活性的成纤维细胞启动，转化生长因子-β1通过上调PAI-1同时下调uPA活性来阻止正常成纤维细胞的纤维蛋白溶解。相比之下，瘢痕疙瘩成纤维细胞表现出内在的高PAI-1水平和低uPA水平。激活剂和抑制剂活性比例的这种变化归因于瘢痕疙瘩成纤维细胞对纤维蛋白降解的改变。通过Northern分析在RNA水平上也证实了PAI-增加。就纤溶酶/纤溶酶原激活物系统在基质重塑中的关键作用而言，瘢痕疙瘩成纤维细胞表现出的PAI-1水平升高可能不仅对纤维蛋白降解改变有重大影响，而且对随后导致瘢痕疙瘩和纤维化的修复步骤也有重大影响。
