PATHOBIOLOGY OF FIBRIN MATRIX IN CHRONIC WOUNDS

这一提议的中心假设是富含纤维蛋白的 正常伤口的临时基质为移行和转移提供了支架 增殖细胞，此外，还可能直接调节细胞功能， 可能会改变细胞对细胞因子的反应，并可能充当 生长因子或细胞因子。我们将测试其中的两个主要推论 假设：I.纤维蛋白基质提供一种细胞因子-- 促进细胞增殖和迁移的丰富环境。正常情况下 皮肤创伤时，纤维蛋白沉积在伤口的缺损处并刺激 局部纤维增生和血管生成。治愈就是结果。在慢性病 静脉溃疡，纤维蛋白异位形成为血管周围的袖带和 促进间充质细胞增殖和周围新基质的形成 这些船只。其结果是，氧气、营养物质和 其他部位的生长因子受到阻碍，愈合受到损害。二、 静脉性溃疡患者的纤维蛋白基质不同于正常伤口的暂时性 生物化学结构和分子含量的矩阵(ECM分子， 细胞因子、蛋白水解酶、蛋白酶抑制物)。这些差异很大 在伤口修复过程中影响成纤维细胞功能。 这些概念并不是相互排斥的。我们建议解决是否 与纤维蛋白或纤维蛋白基质相关的生物反应调节剂 在正常的皮肤创伤和静脉性小腿溃疡中，这一点是不同的。 此外，我们还将研究各种纤维蛋白基质在 其他分子的存在或不存在会影响成纤维细胞的功能。 具体来说，在目标1中，我们将描述富含纤维蛋白的基质和 正常创面和静脉性溃疡中的相关间充质细胞。在AIM 2中 我们将比较不同组成的纤维蛋白基质对 成纤维细胞增殖。在AIM 3中，我们将检查纤维蛋白的影响 不同组成的基质对成纤维细胞迁移的影响。在AIM 4中，我们 将确定不同组成的纤维蛋白基质是否起到 生长因子的蓄水池。

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.