THROMBIN PEPTIDES REGULATING WOUND HEALING

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There is great interest in the possible use of growth factors to accelerate healing of wounds in normal and healing-impaired individuals. Yet, even with high doses and prolonged exposure, many of these factors have minimal efficacy. Thrombin, appears to be a natural initiator of tissue response to injury, causing clot formation, vascular changes, and direct migratory and mitogenic effects on cells. We have discovered that a single topical application of thrombin or the synthetic thrombin receptor-activating peptide, TRAP-508 accelerates healing of full dermal wounds in normal rats and mice, steroid-treated rats, and in genetically diabetic db+/db+ mice. TRAP-508 increases incisional breaking strength up to 80%, accelerating healing by ~4.5 days (1), and enhances closure of open wounds 50 to 100% over than seen in controls. We believe this enhancement reflects an augmentation of signals normally responsible for initiating wound healing. Our objective is to define the cellular and molecular mechanisms by which thrombin and TRAP-508 accelerate wound healing. TRAP-508 is rapidly cleared from wounds, yet it increases leukocyte recruitment, fibroblast proliferation, epithelial cell migration, and vascularization. We will determine effects of thrombin and TRAP-508 on these cells in culture and the mechanisms by which they are initiated. To establish causal relationships between in vitro and in vivo effects, we will determine if receptor antagonists, proteolytic inhibitors, anti-receptor antibodies, or antibodies to cell specific molecules can negate the enhancement of wound healing in animal models. We will also test TRAP-508 in animals depleted of inflammatory cells by antibody treatment. If these treatments negate TRAP effects, specific cell populations will be reintroduced to determine which is responsible for TRAP enhancement. Polyvinyl alcohol sponge implants will be used to measure TRAP effects on specific cells in vivo. Measurements will include: DNA synthesis; matrix deposition; changes in thrombin receptor expression; and synthesis of specific cytokines that may influence later healing events. These studies will define mechanisms by which thrombin and TRAP initiate wound healing. Understanding these mechanisms may lead to better management of chronic wounds and acceleration of healing after surgery or traumatic injury.