PATHOBIOLOGY OF FIBRIN MATRIX IN CHRONIC WOUNDS

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The central hypothesis of this proposal is that the fibrin-rich provisional matrix of normal wounds provides a scaffold for migrating and proliferating cells, and in addition, may directly modulate cell function, may alter cell responsiveness to cytokines, and may act as a reservoir for growth factors or cytokines. We will test two main corollaries of this hypothesis: I. Fibrin matrices regardless of location provide a cytokine- rich milieu that promote cell proliferation and migration. In normal cutaneous wounds, fibrin is deposited in the wound defect and stimulates local fibroplasia and angiogenesis. Healing is the outcome. In chronic venous ulcers, fibrin forms ectopically as cuffs around blood vessels and promotes mesenchymal cell proliferation and neomatrix formation around these vessels. As a consequence, diffusion of oxygen, nutrients, and growth factors to other sites is impeded and healing is impaired. II. Fibrin matrices in venous ulcers differ from normal wound provisional matrix in biochemical structure and molecular content (ECM molecules, cytokines, proteases, protease inhibitors). These differences greatly affect fibroblast function during wound repair. These concepts are not mutually exclusive. We propose to address whether biologic response modifiers associated with fibrin, or the fibrin matrix itself, differs in normal cutaneous wounds and venous leg ulcers. Additionally we will investigate how various fibrin matrices, in the presence or absence of other molecules, affect fibroblast function. Specifically in AIM 1 we will characterize the fibrin-rich matrix and associated mesenchymal cells in normal wounds and venous ulcers. In AIM 2 we will compare the effects of fibrin matrices of differing composition on fibroblast proliferation. In AIM 3 we will examine the effects of fibrin matrices of differing composition on fibroblast migration. In AIM 4 we will determine whether fibrin matrices of differing composition act as reservoirs for growth factors.