Gillard Judith A, Reed Malcolm W R, Buttle David, Cross Simon S, Brown Nicola J
Academic Unit of Surgical Oncology, School of Medicine and Biomedical Sciences, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom.
Wound Repair Regen. 2004 May-Jun;12(3):295-304. doi: 10.1111/j.1067-1927.2004.012314.x.
Proteolytic activity is required for the turnover of the extracellular matrix during wound healing. Matrix metalloproteinases can collectively cleave all components of the extracellular matrix, with the endogenous tissue inhibitor of metalloproteinase-1 regulating their activity. Breast tissue taken at varying postoperative times (n= 92) or during surgery (controls, n= 17), was used to investigate the temporal and spatial activity of matrix metalloproteinase-2 and -9 and tissue inhibitor of metalloproteinase-1 during human wound healing. Matrix metalloproteinase activity, determined using a quenched fluorescence substrate assay, increased during early healing (3-8 weeks) compared to controls, and then decreased between 24 and 36 weeks after surgery (p < 0.05 until 24 weeks, Mann-Whitney U-test). Immunohistochemistry scores for matrix metalloproteinase-9 expression were significantly elevated compared to controls in scar endothelial cells and fibroblasts from 2 until 12 and 20 weeks, respectively. Matrix metalloproteinase-2 staining was observed exclusively in fibroblasts, reaching maximum levels 8-12 weeks after surgery, decreasing by 1.5 years but remaining significantly increased. Tissue inhibitor of metalloproteinase-1 staining was relatively sparse but was significantly increased until 8 weeks after surgery. These results show that matrix metalloproteinases are present at elevated levels during early wound healing, when angiogenesis occurs, and suggest that matrix metalloproteinase-9 may play a significant role. The later expression of matrix metalloproteinase-2 and -9 in fibroblasts suggests a role in extracellular matrix remodeling.
在伤口愈合过程中，细胞外基质的更新需要蛋白水解活性。基质金属蛋白酶可共同裂解细胞外基质的所有成分，而金属蛋白酶组织抑制因子-1可调节其活性。本研究使用在不同术后时间（n = 92）或手术期间采集的乳腺组织（对照组，n = 17），来研究基质金属蛋白酶-2、-9以及金属蛋白酶组织抑制因子-1在人类伤口愈合过程中的时空活性。与对照组相比，采用淬灭荧光底物分析法测定的基质金属蛋白酶活性在愈合早期（3 - 8周）升高，然后在术后24至36周下降（直到24周，p < 0.05，Mann-Whitney U检验）。基质金属蛋白酶-9表达的免疫组织化学评分在瘢痕内皮细胞和成纤维细胞中分别从2周直到12周和20周均显著高于对照组。仅在成纤维细胞中观察到基质金属蛋白酶-2染色，在术后8 - 12周达到最高水平，到1.5年时下降，但仍显著升高。金属蛋白酶组织抑制因子-1染色相对较少，但直到术后8周显著增加。这些结果表明，在血管生成发生的伤口愈合早期，基质金属蛋白酶水平升高，提示基质金属蛋白酶-9可能起重要作用。基质金属蛋白酶-2和-9在成纤维细胞中的后期表达提示其在细胞外基质重塑中发挥作用。
