Role(s) of VEGF in Resolution of Inflammation

项目总结 炎症是正常伤口修复的关键过程。一旦受伤，细胞因子就会被激活 和化学吸引白细胞，包括巨噬细胞，伤口部位。巨噬细胞是关键 有利于肉芽组织的正常形成，因为它们能清除伤口中的死亡细胞 并产生过多的细胞因子，启动愈合组织的形成。虽然很多人 早期参与炎症的详细机制是已知的，那些参与解决 人们对炎症知之甚少。了解炎症是如何结束的与 理解它的开始是因为炎症的延长会导致愈合受损和 慢性炎症状态。血管内皮生长因子是伤口愈合的关键因素，人们主要知道 因为它在血管生成中的作用。然而，最近，血管内皮生长因子正在成为一种免疫调节剂。 和炎症。我们发现，血管内皮生长因子有助于巨噬细胞的分解- 在伤口愈合过程中诱导炎症，并刺激巨噬细胞凋亡 文化。我们还发现，血管内皮细胞生长因子刺激肿瘤坏死因子14/光的表达。 人类巨噬细胞。莱特是已知的肿瘤坏死因子超家族的成员 调节黏膜肿瘤中T细胞的共刺激和细胞凋亡。我们的发现指出 参与炎症反应消退的一种新的细胞因子调节途径。在 我们在这里提出的工作解决了这些新发现的功能的后果 血管内皮生长因子在伤口愈合过程中的消炎作用。我们假设一本小说 血管内皮生长因子在修复过程中的作用是调节巨噬细胞在损伤中的存活 组织，而光是这一过程的关键媒介。具体来说，我们将：(1)确定 血管内皮生长因子是否在体内诱导巨噬细胞凋亡并刺激LIGH表达 愈合过程中和(2)确定血管内皮生长因子诱导的巨噬细胞 细胞死亡与光明。我们将使用培养的人类巨噬细胞的组合，正常和 转基因小鼠，结合血管内皮生长因子激动剂/拮抗剂和光依赖 小路。组织化学和免疫学技术、酶联免疫吸附试验、多重RT-PCR和siRNA 将使用技术。提出的工作是新颖的，因为它揭示了以前未知的东西 血管内皮生长因子的功能和它的重要性，因为它可以促进新疗法的开发 用于愈合不良的伤口以及其他以过度炎症为特征的情况 对于血管内皮生长因子表达上调的肿瘤。因为炎症的消退很差 在大多数不正常的愈合情况下，这一调查对健康具有重要意义 因为它确定了一种改善受损愈合的新策略，这是一个关键的医疗领域。

PROJECT SUMMARY Inflammation is a key process in normal wound repair. Upon wounding, cytokines are activated and chemoattract leukocytes, including macrophages, to the wound site. Macrophages are key for the proper formation of granulation tissue because they clean up dead cells in the wound and produce a plethora of cytokines that initiate formation of the healing tissue. While many detailed mechanisms involved early in inflammation are known, those involved in resolution of inflammation are poorly understood. Understanding how inflammation ends is as important as understanding its beginning because prolongation of inflammation leads to impaired healing and chronic inflammatory conditions. VEGF is a key factor in wound healing and is primarily known for its role in angiogenesis. However, recently VEGF is emerging as a regulator of immunity and inflammation. We have discovered that VEGF contributes to resolution of macrophage- induced inflammation during wound healing and that it stimulates macrophage apoptosis in culture. We have also shown that VEGF stimulates the expression of TNFSF14/LIGHT in human macrophages. LIGHT is a member of the TNF superfamily of cytokines known to regulate co-stimulation of T cells as well as apoptosis in mucosal tumors. Our findings point to a novel cytokine-modulated pathway involved in resolution of the inflammatory response. In the work proposed here we address the consequences of these newly discovered functions of VEGF in resolution of inflammation during wound healing. We hypothesize that a novel function of VEGF in the healing process is modulation of macrophage survival in the damaged tissue and that LIGHT is a critical mediator of this process. Specifically, we will: (1) Determine whether VEGF induces macrophage apoptosis in vivo and stimulates LIGHT expression during healing and (2) Determine the relationship between VEGF-induced macrophage cell death and LIGHT. We will use a combination of cultured human macrophages, normal and genetically-modified mice, coupled with agonists/antagonists of VEGF- and LIGHT-dependant pathways. Histochemical and immunological techniques, ELISA, multiplex RT-PCR and siRNA technology will be used. The work proposed is novel because it reveals previously unknown functions of VEGF and it is important because it may facilitate the development of new therapies for poorly-healing wounds as well as other conditions characterized by excessive inflammation and for tumors in which VEGF is upregulated. Because resolution of inflammation occurs poorly or not at all in most abnormal healing situations, this line of investigation is significant for health because it identifies a novel strategy for improving impaired healing, a critical medical area.