PATHOBIOLOGY OF FIBRIN MATRIX IN CHRONIC WOUNDS

这项提议的核心假设是， 正常伤口的临时基质提供了用于迁移的支架， 增殖细胞，并且另外，可以直接调节细胞功能， 可以改变细胞对细胞因子的反应性，并可以作为储存库， 生长因子或细胞因子。我们将检验两个主要的推论 假设：I.无论位置如何，纤维素基质都提供细胞因子- 丰富的环境，促进细胞增殖和迁移。 正常 在皮肤伤口中，纤维蛋白沉积在伤口缺损处， 局部纤维增生和血管生成。治愈是结果。慢性 静脉溃疡，纤维蛋白异位形成血管周围的袖口， 促进周围间充质细胞增殖和新基质形成 这些船只。 因此，氧气、营养物质和 生长因子向其它部位的转移受阻，愈合受损。二. 静脉性溃疡中的纤维基质与正常伤口试模不同 生物化学结构和分子含量中的基质（ECM分子， 细胞因子、蛋白酶、蛋白酶抑制剂）。这些差异极大 影响伤口修复过程中的成纤维细胞功能。 这些概念并不相互排斥。我们建议， 与纤维蛋白或纤维蛋白基质相关的生物反应调节剂 其本身在正常皮肤伤口和静脉性腿部溃疡中不同。 此外，我们将研究各种纤维蛋白基质， 其他分子的存在或不存在影响成纤维细胞功能。 特别是在AIM 1中，我们将表征富含纤维蛋白的基质， 相关的间充质细胞在正常伤口和静脉溃疡。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， 将确定不同组成的纤维蛋白基质是否作为 储存生长因子。

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.