Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds
Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds
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DOI：
10.1016/j.yexcr.2004.06.007
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发表时间：
2004-10-01
影响因子：
3.7
通讯作者：
Ågren, MS
中科院分区：
文献类型：
--
作者：
Mirastschijski, U;Haaksma, CJ;Ågren, MS
在这项研究中，我们研究了基质金属蛋白酶（MMP）对上皮形成，肉芽组织发育，伤口收缩和α-平滑肌肌动蛋白（ASMA）表达的影响，在皮肤伤口修复过程中，通过全身施用合成的广谱MMP抑制剂GM 6001（N-[（2 R）-2-（羟氨基羰基甲基）-4-甲基戊酰基]-L-色氨酸甲酰胺）。22只雌性Sprague-Dawley大鼠背部的4个全层切除伤口（50 mm（2）），其中12只用GM 6001 100 mg/kg治疗，10只用溶剂治疗，通过继发性愈合。GM 6001处理的伤口用新上皮最低限度地重新表面化，尽管伤口边缘中的角质形成细胞增殖未改变，而对照伤口在创伤后第7天完全覆盖有3-7层角质化不全的上皮细胞。羟脯氨酸浓度，胶原蛋白的标志物，和肉芽组织中的细胞增殖没有显着差异GM 6001处理组和对照组。受损的伤口收缩（P < 0.01）与GM 6001伤口肉芽组织中ASMA阳性肌成纤维细胞的急剧减少有关。这不是由于GM 6001阻断了转化生长因子-β 1（TGF+ β 1）诱导的肌成纤维细胞分化，因为GM 6001在培养的大鼠真皮成纤维细胞中不抑制TGF-β 1诱导的ASMA表达和力的产生。非选择性MMP抑制剂GM 6001对皮肤修复的严重损害表明角质形成细胞表面重塑、伤口收缩和肉芽组织组织化是高度依赖于NMP的过程。(C)2004年爱思唯尔公司All rights reserved.
In this study, we examined the impact of matrix metalloproteinases (MMP) on epithelialization, granulation tissue development, wound contraction, and alpha-smooth muscle actin (ASMA) expression during cutaneous wound repair through systemic administration of the synthetic broad-spectrum MMP inhibitor GM 6001 (N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide). Four full-thickness excisional wounds (50 mm(2)) on the back of 22 young female Sprague-Dawley rats, 12 treated with GM 6001 100 mg/kg and 10 with vehicle, were allowed to heal by secondary intention. GM 6001-treated wounds were minimally resurfaced with neoepithelium, despite unaltered keratinocyte proliferation in wound edges, whereas control wounds were completely covered with 3-7 cell layers of parakeratinized epithelium on post-wounding day 7. Hydroxyproline concentration, a marker of collagen, and cell proliferation in granulation tissue did not differ significantly between GM 6001-treated and control groups. Impaired wound contraction (P < 0.01) was associated with a dramatic reduction of ASMA-positive myofibroblasts in granulation tissue of GM 6001 wounds. This was not due to GM6001 blocking transforming growth factor-beta1 (TGF+beta1)-induced myofibroblast differentiation since GM 6001 did not inhibit TGF-beta1-induced ASMA expression and force generation in cultured rat dermal fibroblasts. The profound impairment of skin repair by the nonselective MMP inhibitor GM 6001 suggests that keratinocyte resurfacing, wound contraction, and granulation tissue organization are highly NIMP-dependent processes. (C) 2004 Elsevier Inc. All rights reserved.