THROMBIN IN WOUND HEALING--MULTIPLE FUNCTIONS

凝血酶是一种调节性胰蛋白酶样丝氨酸蛋白酶， 它在血液凝固中的主要功能，已被证明具有 在伤口愈合过程中发挥额外功能的潜力。 其他建议的凝血酶功能包括1）直接介导 血管流动; 2）巨噬细胞的趋化活性，也许， 嗜中性粒细胞和3）成纤维细胞的促有丝分裂活性。 此外 由凝血酶从血小板释放的物质，如血小板反应蛋白， 血小板源性生长因子在创伤愈合中起重要作用 过程 因此，除了两个基本反应之外， 保护血管完整性，凝血纤维蛋白原， 凝血酶在血小板聚集中具有广泛和多样的作用， 伤口愈合过程。 本提案所述研究的重点是 研究这些不同活动的结构关系。 特别是有限的蛋白质水解和特定的化学物质的组合 修改将用于研究结构的关系， 人凝血酶上特异性与 纤维蛋白原、纤维蛋白、血小板、血栓调节蛋白和凝血酶原片段2。 影响凝血酶被纤维蛋白吸收的因素及后续研究 将阐明平衡释放。 这部分研究是 特别重要的是在测试的假设，凝血酶是 通过纤维蛋白和伤口部位浓缩，用于随后的愈合过程。 嗜中性粒细胞和巨噬细胞在伤口愈合中至关重要， 将进行研究以确定纤维蛋白结合凝血酶是否 保持趋化活性。 最后，血小板释放的物质 将评价其对以下方面的定量影响： 凝血酶的生物调节作用。 从这些获得的结果 研究将允许更合理地开发增强因素， 正常和受损个体的伤口愈合。

Thrombin, a regulatory tryptic-like serine protease, well recognized for its cardinal function in blood coagulation, has been demonstrated to have the potential for additional function(s) in the wound-healing process. Other suggested functions for thrombin include 1) direct mediation of vascular flow; 2) chemotactic activity for macrophages and, perhaps, neutrophils and 3) mitogenic activity for fibroblasts. Furthermore materials released from platelets by thrombin, such as thrombospondin and platelet-derived growth factor, play an important role in the would-healing process. Thus, beyond the two basic reactions fundamental for the preservation of vascular integrity, the clotting of fibrinogen and aggregation of platelets, thrombin has a broad and diverse role in the wound healing process. The focus on the research described in the present proposal is directed at the study of the structural relationships of these various activities. Specifically a combination of limited proteolysis and specific chemical modification will be used to study the relationship of structural determinants on human thrombin which are specific for interaction with fibrinogen, fibrin, platelets, thrombomodulin and prothrombin fragment 2. Factors influencing the absorption of thrombin to fibrin and subsequent equilibrium release will be elucidated. This portion of the study is of particular importance in the testing of the hypothesis that thrombin is concentrated by fibrin and the wound-site for subsequent healing process. Neutrophils and macrophages are of critical importance in wound-healing and studies will be performed to determine whether fibrin-bound thrombin retains chemotactic activity. Finally, material released from platelets during coagulation will be evaluated for their quantitative effect(s) on the bioregulatory action of thrombin. The results obtained from these studies will permit the more rationale development of enhancing factors for wound-healing in normal and compromised individuals.