Wound Reepithelialization

Rapid wound epithelialization, the migration of ker-atinocytes to seal an open wound, is considered by many to be a good predictor of successful wound healing. A fully epithelialized wound is more likely to heal. Keratinocytes begin this process by invading the provisional clot made of fibrin and fibronectin. Plasmin is upregulated soon after wounding, presumably for breaking down the fibrin clot. Indeed, plasminogen knockout mice demonstrate significantly diminished wound reepithelialization [4]. Other degradation enzymes, such as matrix metalloproteinase (MMP)-1, -9, and -10, are also upregulated around wound edges. Analysis of chronic wound fluid revealed high levels of proteolytic activity from MMPs, suggesting that their overexpression retards wound healing. In normal wound healing, epithelial cells stretch and divide to cover a denuded wound surface with a single layer of cells. Once a single epithelial cell layer has been established, in a process inhibited through integrin signaling and contact inhibition, keratinocyte proliferation ceases.

Fibronectin, which binds fibrin, is a potent stimulus of keratinocyte migration. The a-3, b-1 integrin fibronectin receptor is upregulated in keratinocytes after wounding, suggesting that it is important in keratinocyte migration. The fragment of fibronectin that binds to keratinocytes has been found in large quantities in wounds and has been shown to stimulate monocyte and fibroblast chemotaxis through the dermis [5]. Indeed, it appears that the invasive/migratory phenotype expressed by epithelial cells and fibroblasts after wounding may be the result of interactions between this soluble fibronectin fragment and a-3, b-1 integrin signaling. Topical application to this fragment has been shown to accelerate wound healing in diabetic obese mice.

Epidermal growth factor (EGF), transforming growth factor-a, and heparin binding-EGF are all part of the EGF superfamily and have been considered key regulators of keratinocyte proliferation. All three of these factors are released in abundance at the site of injury. Application of the first two to burnt pig skin hastens the reepithelization process. Other stimulants of epithelialization include keratinocyte growth factor (KGF), which is upregulated one-hundredfold in normal wound margins but significantly less in those of diabetic wounds and steroid-treated wounds. Surprisingly, however, KGF knockout mice do not exhibit delayed reep-ithelialization. This is thought to be secondary to redundancy since mice with the dominant mutant KGF receptor demonstrate significantly delayed wound healing. Application of exogenous KGF also has rate-enhancing effects with increased expression of tissue type plasminogen activator and MMP-10. Furthermore, transplantation of both normal and transgenic keratinocytes into full-thickness wounds has improved wound healing.

Surgeons have long known that a key factor in wound healing is excellent tissue perfusion. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and TGF-b are the critical factors involved in wound angiogen-esis. VEGF is expressed at low levels in normal skin but highly upregulated in keratinocytes during wound healing. Angiogenesis appears to be tied to matrix deposition and granulation tissue formation. Application of a neutralizing anti-VEGF antibody to a wound is associated with decreased wound angiogenesis. Conversely, application of topical VEGF increases wound angiogenesis, granulation tissue formation, and wound closure rates [6]. Diabetic wounds are found to have decreased levels of VEGF expression, but demonstrate very high levels of angiopoetin-2, an antiangiogenic protein. Although angiopoetin-2 production in wounds is not unusual during specific phases of wound healing when vessel growth requires destabilizing preexisting vessels, such high levels are not usually seen. The impaired angiogenesis observed in diabetic mice is thought mainly to be due to free radical mediated lipid peroxidation, dysfunctional keratinocytes, and a resultant decreased endo-thelial cell VEGF production.

TGF-b is a multipurpose growth factor expressed ubiquitously during wound healing, but its major roles are the stimulation of endothelial cell migration and matrix deposition. There are several different TGF-b isoforms, but they interestingly all bind to the same receptor. TGF-bl is expressed early on in wound healing, whereas TGF-P3 is expressed late. TGF-P3 has also been shown to decrease scarring. Despite the expectedly decreased matrix deposition in TGF-b-receptor 1 deficient animals, increased wound angiogenesis is observed. This apparent paradox highlights the apparently contradictory effects of TGF-b in a wound and in culture. TGF-b inhibits angiogenesis in vitro, whereas the opposite occurs in vivo.

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