THROMBIN IN WOUND HEALING--MULTIPLE FUNCTIONS

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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.