ARGININE CELL FUNCTION CONTROL IN WOUND HEAL

成功的伤口愈合需要协调的活动， 多种细胞类型，构成炎症和修复 对组织损伤的反应。生长因子的鉴定， 细胞因子、细胞外基质成分和其它化合物 存在于伤口中的药物有望临床应用， 在愈合过程中进行积极的治疗干预。的 这些应用程序的合理开发反过来又要求， 更好地理解炎症性细胞的细胞生物学， 细胞，最具体地说，因为它涉及其调制， 伤口环境特有的条件。这是基础 炎症细胞功能的调节不能 要充分理解，除非环境的特殊性， 这些细胞的生存、接收和对特定信号的反应是 考虑到。在这方面，在这个实验室工作 证明了愈合伤口的一个突出特征是 代谢导致精氨酸浓度降低 这种氨基酸通过一氧化氮的诱导形式 合酶（iNOS）和腺苷酸酶，这两种酶是 在伤口中以暂时分离的方式表达。iNOS是 在炎症的非常早期阶段显著表达 而酶是唯一可检测到的高通量酶的一个？吉宁 在伤口中的代谢在占主导地位的时间 巨噬细胞/成纤维细胞浸润。此时iNOS表达是 被伤口中占优势的条件主动抑制， 包括上述降低的精氨酸浓度， 缺氧和存在于伤口流体中的分子。是中央 这一假说认为iNOS是一种“禁止途径”， 愈合伤口，因为它的产品抑制细胞功能 与维修相关（即：巨噬细胞吞噬作用，成纤维细胞 增殖和胶原沉积），并最终介导细胞 死亡为了验证这一假设，本项目的具体目标 旨在定义巨噬细胞的功能表型 从大鼠实验伤口中获得;评估影响 精氨酸的利用率，伤口液体和细胞外基质 获得和维持这种表型的成分; 研究精氨酸和NO在调节 巨噬细胞/成纤维细胞的相互作用;并定义的机制， 与NO产生相关的代谢损伤。 此外，本文提出的工作将探讨细胞凋亡的作用， 以及通过创伤从创伤中去除凋亡细胞 巨噬细胞在炎症的终止和修复。

Successful wound healing requires the coordinated activities of the multiple cell types that constitute the inflammatory and reparatory response to tissue injury. The identification of growth factors, cytokines, extracellular matrix components and other compounds present in the wound promises clinical applications that will allow active therapeutic intervention during the healing process. The rational development of these applications will require, in turn, a better understanding of the cell biology of the inflammatory cells, most specifically as it relates to its modulation by conditions unique to the wound environment. It is the basis of this proposal that the regulation of inflammatory cell function cannot be fully understood unless the peculiarities of the environment in which these cells live and receive and react to specific signals is taken into consideration. In this regard, work in this laboratory demonstrated that a prominent feature of healing wounds is a decreased arginine concentration that results from the metabolism of this amino acid through the inducible form of nitric oxide synthase (iNOS) and arginase, and that these two enzymes are expressed in the wound in a temporally segregated manner. iNOS is expressed prominently during the very early phases of inflammation and arginase is the only detectable high-flux enzyme of a?ginine metabolism in the wound at the time of predominant macrophage/fibroblast infiltration. iNOS expression at-that time is actively suppressed by conditions prevailing in the wound, including the aforementioned reduced arginine concentration, hypoxia and by molecules present in wound fluid. It is the central hypothesis o this proposal that iNOS is a "forbidden pathway" in healing wounds because its products suppress cell functions relevant to repair (i.e.: macrophage phagocytosis, fibroblast proliferation and collagen deposition) and ultimately mediate cell death. To test this hypothesis, the Specific Aims of this prpposal are designed to define the functional phenotype of macrophages obtained from experimental wounds in the rat; evaluate the impact of arginine availability, wound fluids and extracellular matrix components in the acquisition and maintenance of this phenotype; investigate the role of arginine and NO in the regulation of macrophage/fibroblast interactions; and define the mechanisms of metabolic injury associated with the production of NO. Additionally, work proposed here will explore the role of apoptosis and the removal of apoptotic cells from the wound by wound macrophages in the termination of inflammation and repair.