Urokinase-type plasminogen activator stimulates wound healing in the diabetic mouse
Urokinase-type plasminogen activator stimulates wound healing in the diabetic mouse
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尿激酶型纤溶酶原激活剂刺激糖尿病小鼠伤口愈合
DOI：
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发表时间：
1997
影响因子：
6.7
通讯作者：
M. J. Antonaccio
中科院分区：
文献类型：
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作者：
P. Jimenez;M. Teliska;B. Liu;M. J. Antonaccio
伤口愈合受损是人类发病率的重要来源。与人类一样，纯合子糖尿病（C57 BL/ KsJ db/db）小鼠表现出受损的伤口愈合。由于4号染色体上的单个常染色体隐性突变，这些动物出现耐药性高血糖、肥胖、多尿和多食[1]。皮肤损伤引发一系列事件，包括炎症、细胞迁移、重塑和基质形成[2]。在这一过程中的防御构成了严重的威胁，因此鼓励寻求治疗干预。细胞降解、炎症、血管生成和角质形成细胞分化所需的纤溶酶原激活物（PA）/纤溶酶系统在伤口修复期间角质形成细胞的迁移中起重要作用[3]。角质形成细胞合成并分泌尿激酶型纤溶酶原激活物（uPA），其在创伤修复期间在迁移的角质形成细胞中表达。uPA和尿激酶纤溶酶原激活物受体（uPAR）在正常表皮中均不表达，并且在皮肤修复后下调。受体结合uPA（uPAR）在上皮再生过程中在伤口边缘启动局灶性细胞外蛋白水解[4]。缺乏纤溶酶原的小鼠会出现具有纤维蛋白沉积物的不愈合皮肤溃疡[5]。在糖尿病小鼠模型中研究了uPA的愈合作用。突变型C57 BL/KsJdb/db糖尿病小鼠作为受损伤口愈合的模型已被广泛研究。这种损害的特征是细胞浸润、成纤维细胞、肉芽组织和上皮再生延迟[6]。因此，对其损害的机制知之甚少。在这份报告中，我们表明，局部应用uPA的全层伤口加速受损的糖尿病小鼠（db=db）和他们的正常同窝仔（db=m）的愈合过程。
Impaired wound healing is a significant source of morbidity in humans. As in humans, the homozygous diabetic (C57BL/ KsJ db/db) mouse exhibits impaired wound healing. These animals develop resistant hyperglycemia, obesity, polyuria and polyphagia, as a result of a single autosomal recessive mutation on chromosome 4 [1]. Injury to the skin initiates a sequence of events comprised of inflammation, cell migration, remodeling and matrix formation [2]. Deficiencies in this process pose serious threats and have consequently encouraged the search for therapeutic intervention. The plasminogen activator(PA)/plasmin system, required for cellular degradation, inflammation, angiogenesis and keratinocyte differentiation, plays an important role in the migration of keratinocytes during wound repair [3]. Keratinocytes synthesize and secrete urokinase-type plasminogen activator (uPA), which is expressed in migrating keratinocytes during wound repair. Neither uPA nor urokinase plasminogen activator receptor (uPAR) is expressed in normal epidermis and are down-regulated upon restoration of skin. Receptor bound uPA (uPAR) initiates focal extracellular proteolysis at the wound edge during re-epithelialization [4]. Mice deficient in plasminogen develop non-healing skin ulcers with fibrin deposits [5]. The healing effects of uPA were studied in the diabetic mouse model. The mutant C57BL/KsJdb/db diabetic mouse has been extensively studied as a model of impaired wound healing. This impairment is characterized by delay in cellular infiltrate, fibroblasts, granulation tissue and reepithelialization [6]. Thus, the mechanism for their impairment is poorly understood. In this report we show that topically applied uPA on full-thickness wounds accelerates the healing process in both impaired diabetic mice ( db=db) and their normal littermates ( db=m).