Defective extracellular matrix reorganization by chronic wound fibroblasts is associated with alterations in TIMP-1, TIMP-2, and MMP-2 activity

被引:142
作者
Cook, H
Stephens, P
Davies, KJ
Harding, KG
Thomas, DW [1 ]
机构
[1] Univ Wales Coll Med, Sch Dent, Dept Oral Surg Med & Pathol, Cardiff CF14 4XY, S Glam, Wales
[2] Univ Wales Coll Med, Dept Surg, Wound Healing Res Unit, Cardiff CF14 4XY, S Glam, Wales
关键词
chronic wound healing; extracellular matrix reorganization; fibroblast populated collagen lattice; matrix metalloproteinase;
D O I
10.1046/j.1523-1747.2000.00044.x
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
Chronic leg wounds are characterized by defective remodeling of the extracellular matrix, failure of reepithelialization, and prolonged inflammation. The hypothesis that this defective extracellular matrix remodeling is associated with phenotypic differences in the activity of the matrix metalloproteinases and tissue inhibitors of metalloproteinases was studied in chronic wound and patient-matched normal fibroblasts in three-dimensional collagen lattice systems. Chronic wound fibroblasts exhibited no differences in morphology or proliferation (p > 0.1) compared with patient-matched uninvolved dermal fibroblasts. The ability of chronic wound fibroblasts to reorganize extracellular matrix was significantly impaired, however, in comparison to the uninvolved dermal fibroblasts (p < 0.01). This difference in extracellular matrix reorganization was not related to differences in proliferation within the collagen lattices (p > 0.05) or attachment to type I collagen (p > 0.1). Marked differences were evident in matrix metalloproteinase-2 activity between chronic wound and patient-matched normal fibroblasts. Whereas levels of pro-matrix metalloproteinase-2 were similar between the two fibroblast populations (p > 0.1), the chronic wound fibroblasts exhibited significantly decreased levels of the 62 kDa active form of matrix metalloproteinase-2 (p < 0.01). Reverse zymography and enzyme-linked immunosorbent assay demonstrated that the decreased matrix metalloproteinase-2 activity was associated with increased production of tissue inhibitors of metalloproteinase-1 and -2 by the chronic wound fibroblasts (p < 0.05). Increased production of tissue inhibitors of metalloproteinases in chronic wound fibroblasts was also reflected in decreased levels of matrix metalloproteinase-1 (p < 0.005). These data suggest that the impaired ability of chronic wound fibroblasts to reorganize extracellular matrix in vitro is related to decreased levels of active matrix metalloproteinase-2 and matrix metalloproteinase-1 resulting from increased production of tissue inhibitors of metalloproteinase-1 and -2 by chronic wound fibroblasts. These findings provide a mechanism to explain the impaired cellular responses and extracellular matrix reorganization observed in chronic leg wounds in vivo.
引用
收藏
页码:225 / 233
页数:9
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