Lund L R, Romer J, Bugge T H, Nielsen B S, Frandsen T L, Degen J L, Stephens R W, Danø K
The Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, DK-2100 Copenhagen O, Denmark.
EMBO J. 1999 Sep 1;18(17):4645-56. doi: 10.1093/emboj/18.17.4645.
Retarded wound healing was found in mice deficient in the serine protease precursor plasminogen, as well as in wild-type mice treated with the metalloprotease inhibitor galardin, but in both cases wound closure was ultimately completed in all mice within 60 days. The expression of several matrix metalloproteases in keratinocytes migrating to cover the wound was strongly enhanced by galardin treatment. However, when plasminogen-deficient mice were treated with galardin, healing was completely arrested and wound closure was not seen during an observation period of 100 days, demonstrating that protease activity is essential for skin wound healing. The requirement for both plasminogen deficiency and metalloprotease inhibition for complete inhibition of the healing process indicates that there is a functional overlap between the two classes of matrix-degrading proteases, probably in the dissection of the fibrin-rich provisional matrix by migrating keratinocytes. Each class alone is capable of maintaining sufficient keratinocyte migration to regenerate the epidermal surface, although this function would normally be performed by both classes acting in parallel. Since there are strong similarities between the proteolytic mechanisms in wound healing and cancer invasion, these results predict that complete arrest of this latter process in therapeutic settings will require the use of inhibitors of both classes of proteases.
在缺乏丝氨酸蛋白酶前体纤溶酶原的小鼠以及用金属蛋白酶抑制剂加拉丁处理的野生型小鼠中，发现伤口愈合延迟，但在这两种情况下，所有小鼠的伤口最终都在60天内愈合。加拉丁处理强烈增强了迁移以覆盖伤口的角质形成细胞中几种基质金属蛋白酶的表达。然而，当用加拉丁处理纤溶酶原缺陷型小鼠时，愈合完全停止，在100天的观察期内未见伤口闭合，这表明蛋白酶活性对皮肤伤口愈合至关重要。完全抑制愈合过程对纤溶酶原缺乏和金属蛋白酶抑制的双重需求表明，这两类基质降解蛋白酶之间存在功能重叠，可能在迁移的角质形成细胞分解富含纤维蛋白的临时基质过程中。单独每一类都能够维持足够的角质形成细胞迁移以再生表皮表面，尽管这种功能通常由两类蛋白酶并行发挥作用来完成。由于伤口愈合和癌症侵袭中的蛋白水解机制有很强的相似性，这些结果预测，在治疗环境中完全阻止后者的过程将需要使用两类蛋白酶的抑制剂。
