Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice
Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice
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DOI：
10.2119/molmed.2009.00171
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发表时间：
2010-02
影响因子：
5.7
通讯作者：
Zhi Xu;Haifeng C. Xu;V. Ploplis;F. Castellino
中科院分区：
文献类型：
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作者：
Zhi Xu;Haifeng C. Xu;V. Ploplis;F. Castellino
皮肤角质形成细胞表达组织因子（TF），并且与皮肤伤口愈合高度相关。尽管已证明真皮损伤后形成的肉芽组织中血管周围TF表达在愈合过程中下调，但缺乏对TF配体因子（F）VII在皮肤伤口愈合中的机制的研究。我们报告了使用皮肤穿孔模型来证明与野生型对照相比，低表达FVII小鼠（野生型[WT]的约1%）表现出受损的皮肤伤口愈合。这些低FVII小鼠在伤口部位表现出有缺陷的上皮再生和减少的炎性细胞浸润。这种减弱的上皮再生与转录因子早期生长反应1（Egr-1）的表达减少有关。在体外，Egr-1被证明是必不可少的FVIIa诱导的角质形成细胞迁移和炎症的调节。角质形成细胞中的Egr-1上调和下游炎性细胞因子的出现都依赖于FVIIa/TF/蛋白酶激活受体2（PAR-2）诱导的信号传导，并且不需要随后产生FXa和凝血酶。通过使用Egr-1缺陷小鼠证实了Egr-1参与FVIIa介导的角质形成细胞功能调节，其中相对于WT小鼠，观察到损伤后皮肤伤口愈合的显著延迟。这些研究的结果表明，在伤口愈合过程中，FVIIa、Egr-1和角质形成细胞功能中的炎症反应之间存在体内机制关系。
Skin keratinocytes express tissue factor (TF) and are highly associated with skin wound healing. Although it has been demonstrated that perivascular TF expression in granulation tissue formed after dermal injury is downregulated during healing, studies of the mechanism of factor (F) VII, a TF ligand, in skin wound healing are lacking. We reported the use of a dermal punch model to demonstrate that low-expressing FVII mice (∼1% of wild type [WT]) exhibited impaired skin wound healing compared with WT controls. These low-FVII mice showed defective reepithelialization and reduced inflammatory cell infiltration at wound sites. This attenuated reepithelialization was associated with diminished expression of the transcription factor early growth response 1 (Egr-1). In vitro, Egr-1 was shown to be essential for the FVIIa-induced regulation of keratinocyte migration and inflammation. Both Egr-1 upregulation and downstream inflammatory cytokine appearance in keratinocytes depended on FVIIa/TF/protease-activated receptor 2 (PAR-2)-induced signaling and did not require subsequent generation of FXa and thrombin. The participation of Egr-1 in FVIIa-mediated regulation of keratinocyte function was confirmed by use of Egr-1-deficient mice, wherein a significant delay in skin wound healing after injury was observed, relative to WT mice. The results from these studies demonstrate an in vivo mechanistic relationship between FVIIa, Egr-1 and the inflammatory response in keratinocyte function during the wound healing process.