Elevated levels of plasminogen activator inhibitor-1 may account for the altered fibrinolysis by keloid fibroblasts.
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.
Tuan
T L
TL
Department of Surgery, Childrens Hospital Los Angeles, University of Southern California, School of Medicine, USA.
Zhu
J Y
JY
Sun
B
B
Nichter
L S
LS
Nimni
M E
ME
Laug
W E
WE
D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D007627:Keloid / Q000503:physiopathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000235:genetics
D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D005337:Fibrin; D014568:Urokinase-Type Plasminogen Activator