Weigel P H, Fuller G M, LeBoeuf R D
J Theor Biol. 1986 Mar 21;119(2):219-34. doi: 10.1016/s0022-5193(86)80076-5.
A model is presented outlining the molecular and cellular events that occur during the early stages of the wound healing process. The underlying theme is that there is a specific binding interaction between fibrin, the major clot protein, and hyaluronic acid (HA), a constituent of the wound extracellular matrix. This binding interaction, which could also be stabilized by other cross-linking components, provides the driving force to organize a three-dimensional HA matrix attached to and interdigitated with the initial fibrin matrix. The HA-fibrin matrix plays a major role in the subsequent tissue reconstruction processes. We suggest that HA and fibrin have both structural and regulatory functions at different times during the wound healing process. The concentration of HA in blood and in the initial clot is very low. This is consistent with the proposed interaction between HA and fibrin(ogen), which could interfere with either fibrinogen activation or fibrin assembly and cross-linking. We propose that an activator (e.g. derived from a plasma precursor, platelets or surrounding cells) is produced during the clotting reaction and then stimulates one or more blood cell types to synthesize and secrete HA into the fibrin matrix of the clot. We predict that HA controls the stability of the matrix by regulating the degradation of fibrin. The new HA-fibrin matrix increases or stabilizes the volume and porosity of the clot and then serves as a physical support, a scaffold through which cells trapped in the clot or cells infiltrating from the peripheral edge of the wound can migrate. The HA-fibrin matrix also actively stimulates or induces cell motility and activates and regulates many functions of blood cells, which are involved in the inflammatory response, including phagocytosis and chemotaxis. The secondary HA-fibrin matrix itself is then modified as cells continue to migrate into the wound, secreting hyaluronidase and plasminogen activator to degrade the HA and fibrin. At the same time these cells secrete collagen and glycosaminoglycans to make a more differentiated matrix. The degradation products derived from both fibrin and HA are, in turn, important regulatory molecules which control cellular functions involved in the inflammatory response and new blood vessel formation in the healing wound. The proposed model generates a number of testable experimental predictions.
本文提出了一个模型，概述了伤口愈合过程早期发生的分子和细胞事件。其基本主题是，主要的凝血蛋白纤维蛋白与伤口细胞外基质的成分透明质酸（HA）之间存在特定的结合相互作用。这种结合相互作用也可由其他交联成分稳定，它提供了驱动力，促使形成一个附着于初始纤维蛋白基质并与其相互交错的三维HA基质。HA-纤维蛋白基质在随后的组织重建过程中起主要作用。我们认为，HA和纤维蛋白在伤口愈合过程的不同阶段具有结构和调节功能。血液和初始凝块中HA的浓度非常低。这与HA和纤维蛋白原之间的拟议相互作用一致，该相互作用可能会干扰纤维蛋白原的激活或纤维蛋白的组装及交联。我们提出，在凝血反应过程中会产生一种激活剂（例如源自血浆前体、血小板或周围细胞），然后刺激一种或多种血细胞类型合成并将HA分泌到凝块的纤维蛋白基质中。我们预测，HA通过调节纤维蛋白的降解来控制基质的稳定性。新的HA-纤维蛋白基质增加或稳定了凝块的体积和孔隙率，然后作为一种物理支撑，一个支架，被困在凝块中的细胞或从伤口周边浸润的细胞可以通过它迁移。HA-纤维蛋白基质还积极刺激或诱导细胞运动，并激活和调节参与炎症反应的血细胞的许多功能，包括吞噬作用和趋化作用。随着细胞继续迁移到伤口中，分泌透明质酸酶和纤溶酶原激活剂以降解HA和纤维蛋白，二级HA-纤维蛋白基质本身也会被修饰。与此同时，这些细胞分泌胶原蛋白和糖胺聚糖以形成更具分化性的基质。来自纤维蛋白和HA的降解产物反过来又是重要的调节分子，它们控制着参与愈合伤口炎症反应和新血管形成的细胞功能。所提出的模型产生了许多可测试的实验预测。
