Tissue Factor as a Link Between Wounding and Tissue Repair

Chen, Jiang; Kasper, Michael; Heck, Tobias; Nakagawa, Keigo; Humpert, Per M.; Bai, Ling; Wu, Gang; Zhang, Youming; Luther, Thomas; Andrassy, Martin; Schiekofer, Stephan; Hamann, Andreas; Morcos, Michael; Chen, Baoshen; Stern, David M.; Nawroth, Peter P.; Bierhaus, Angelika

doi:10.2337/diabetes.54.7.2143

Cited by 54 publications

(50 citation statements)

References 63 publications

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“…In addition, many of the serine proteases, for example, thrombin, downstream of FVIIa in the coagulation cascade elicit intracellular signaling, which regulates gene transcripts that are involved in wound healing (38). For example, administration of a 23-residue peptide derived from thrombin has been shown to accelerate wound repair (39), and enhancement of TF expression via gene transfer in wounds in diabetic mice restored the delayed wound closure times found in these mice to those of nondiabetic mice (37).…”

Section: Discussionmentioning

confidence: 99%

“…This is mainly because of two considerations: a therapeutic dosage of FVIIa for bleeding control, as in patients with postoperative refractory bleeding or hemophilia A or B, is typically higher than physiological concentration, and the FVII expression level has been demonstrated to be upregulated during challenges, such as inflammation and malignancy (32,36). In particular, TF expression in cutaneous tissue is upregulated immediately after wounding (37). In addition, although 10 nmol/L of mFVIIa induced significant Egr-1 upregulation in the primary keratinocytes, 50 nmol/L of mFVIIa treatment elicited a more robust response ( Figure 3A).…”

Section: Fviia Signaling Is Mediated Through Egr-1 In Keratinocytesmentioning

confidence: 99%

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Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

Ploplis

et al. 2010

Mol Med

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Fviia Signaling Is Mediated Through Egr-1 In Keratinocytesmentioning

confidence: 99%

Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

Ploplis

et al. 2010

Mol Med

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“…Two full-thickness, circular, incisional wounds were generated as previously described [22]. Briefly, mice were anesthetized using 2.5% avertin per gram body weight, before hair on the skin was shaved and skin was swabbed with alcohol.…”

Section: Methodsmentioning

confidence: 99%

Aging-Dependent Reduction in Glyoxalase 1 Delays Wound Healing

et al. 2013

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Methylglyoxal (MG), the major dicarbonyl substrate of the enzyme glyoxalase 1 (GLO1), is a reactive metabolite formed via glycolytic flux. Decreased GLO1 activity in situ has been shown to result in an accumulation of MG and increased formation of advanced glycation endproducts, both of which can accumulate during physiological aging and at an accelerated rate in diabetes and other chronic degenerative diseases. To determine the physiological consequences which result from elevated MG levels and the role of MG and GLO1 in aging, wound healing in young (≤12 weeks) and old (≥52 weeks) wild-type mice was studied. Old mice were found to have a significantly slower rate of wound healing compared to young mice (74.9 ± 2.2 vs. 55.4 ± 1.5% wound closure at day 6; 26% decrease; p < 0.0001). This was associated with decreases in GLO1 transcription, expression and activity. The importance of GLO1 was confirmed in mice by inhibition of GLO1. Direct application of MG to the wounds of young mice, decreased wound healing by 24% compared to untreated mice, whereas application of BSA modified minimally by MG had no effect. Treatment of either young or old mice with aminoguanidine, a scavenger of free MG, significantly increased wound closure by 16% (66.8 ± 1.6 vs. 77.2 ± 3.1%; p < 0.05) and 64% (40.4 ± 7.9 vs. 66.4 ± 5.2%; p < 0.05), respectively, by day 6. As a result of the aminoguanidine treatment, the overall rate of wound healing in the old mice was restored to the level observed in the young mice. These findings were confirmed in vitro, as MG reduced migration and proliferation of fibroblasts derived from young and old, wild-type mice. The data demonstrate that the balance between MG and age-dependent GLO1 downregulation contributes to delayed wound healing in old mice.

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“…14 TF messenger RNA in cutaneous tissue is up-regulated immediately following wounding in a mouse model. 15 TF expression has also been closely linked to angiogenesis in malignancy. 16,17 Therefore, we expected that TF would be highly expressed near a wound site -especially during angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Perivascular tissue factor is down-regulated following cutaneous wounding: implications for bleeding in hemophilia

McDonald

Yang

Roberts

et al. 2008

Blood

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Healing of skin wounds is delayed in hemophilia B (HB) mice. HB mice do not bleed excessively at wounding, yet rebleed hours to days later. Tissue factor (TF) expression is up-regulated by inflammatory cytokines and has been linked to angiogenesis. We hypothesized that impaired thrombin generation in HB leads to impaired TF expression following injury. Punch biopsies were placed on wild-type (WT) and HB mice. Tissues from wound sites were immunostained for TF. Blood vessels are normally surrounded by a coat of pericytes expressing TF. Surprisingly, within a day after wounding TF disappeared from around nearby vessels; returning after 8 days in WT and 10 days in HB mice. The granulation tissue filling the wound during healing also lacked TF around angiogenic vessels. Thus, perivascular TF expression is downregulated during wound healing. This may prevent thrombosis of neovessels during angiogenesis but renders hemophiliacs vulnerable to hemorrhage during healing.

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Tissue Factor as a Link Between Wounding and Tissue Repair

Cited by 54 publications

References 63 publications

Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

Factor VII Deficiency Impairs Cutaneous Wound Healing in Mice

Aging-Dependent Reduction in Glyoxalase 1 Delays Wound Healing

Perivascular tissue factor is down-regulated following cutaneous wounding: implications for bleeding in hemophilia

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