Increased migration of murine keratinocytes under hypoxia is mediated by induction of urokinase plasminogen activator
Increased migration of murine keratinocytes under hypoxia is mediated by induction of urokinase plasminogen activator
复制标题
DOI：
10.1046/j.1523-1747.2002.19533.x
复制
发表时间：
2002-12-01
影响因子：
6.5
通讯作者：
Groves, RW
中科院分区：
文献类型：
--
作者：
Daniel, RJ;Groves, RW
皮肤创伤的关键后果之一是组织缺氧的发展。最近的数据表明，这是一个有力的刺激增加角质细胞迁移，因此再上皮化，虽然负责这仍然不清楚的机制。在这项研究中，我们已经调查了缺氧，纤溶酶原激活，并在体外伤口愈合之间的关系。暴露角质形成细胞培养物缺氧导致尿激酶纤溶酶原激活物mRNA的上调和随后的尿激酶纤溶酶原激活物介导的纤溶酶原激活的增加，通过间接显色肽测定和纤溶酶原连接酶谱测定。体外角质形成细胞伤口愈合的分析证实，与常氧培养物相比，低氧培养物在16小时后伤口闭合增强。用丝裂霉素C和细胞松弛素B预处理常氧和缺氧培养物表明，在该系统中，伤口闭合是由于角质形成细胞迁移而不是增殖。此外，广谱丝氨酸蛋白酶抑制剂，对氨基苯甲脒，或特定的尿激酶纤溶酶原激活物抑制剂，阿米洛利和WX-293，显着减少伤口闭合缺氧文化和废除伤口闭合缺氧增强。这些数据表明尿激酶纤溶酶原激活剂在低氧角质形成细胞迁移中的核心作用，并表明低氧张力下伤口上皮再生增强的潜在机制。
One of the key consequences of cutaneous wounding is the development of tissue hypoxia. Recent data have suggested that this is a potent stimulus for increased keratinocyte migration and hence re-epithelialization, although the mechanisms responsible for this remain unclear. In this study we have investigated the relationship between hypoxia, plasminogen activation, and in vitro wound healing. Exposure of keratinocyte cultures to hypoxia resulted in upregulation of urokinase plasminogen activator mRNA and a subsequent increase in urokinase plasminogen activator-mediated plasminogen activation, as determined by indirect chromogenic peptide assay and plasminogen-linked zymography. Analysis of keratinocyte wound healing in vitro confirmed enhanced wound closure in hypoxic cultures compared with normoxic cultures after 16 h. Pretreatment of normoxic and hypoxic cultures with mitomycin C and cytochalasin B indicated that in this system wound closure was due to keratinocyte migration rather than proliferation. Addition of the broad-spectrum serine proteinase inhibitor, p-aminobenzamidine, or the specific urokinase plasminogen activator inhibitors, amiloride and WX-293, significantly reduced wound closure in hypoxic cultures and abrogated the hypoxic enhancement of wound closure. These data indicate a central role for urokinase plasminogen activators in hypoxic keratinocyte migration and suggest a potential mechanism for enhanced re-epithelialization of wounds under low oxygen tensions.