Role(s) of VEGF in Resolution of Inflammation

VEGF 在炎症消退中的作用

基本信息

批准号：
7849580
负责人：
MANUELA M. MARTINS-GREEN
金额：
$ 21.96万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7849580
关键词：
Address Affect Agonist Apoptosis Area Cell Death Cells Cessation of life Chronic Clinical Trials Collaborations Complex Coupled Development Enzyme-Linked Immunosorbent Assay Event Funding Granulation Tissue Growth Factor Head Healed Health Histology Human Hypersensitivity Immunity Immunologic Techniques Immunology Impaired wound healing Inflammation Inflammatory Inflammatory Response Investigation Knowledge Lead Length Letters Leukocytes Mediating Mediator of activation protein Medical Modeling Mus Pathway interactions Phase Physiological Processes Process Production Resolution Reverse Transcriptase Polymerase Chain Reaction Role Site Small Interfering RNA T-Lymphocyte TNF gene Technology Testing Time Tissues Up-Regulation Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Wild Type Mouse Work Wound Healing angiogenesis cell type cytokine healing improved in vivo macrophage member novel novel strategies public health relevance receptor tumor tumor growth wound

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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. Understanding how inflammation ends is as important as understanding its beginning because prolongation of inflammation leads to impaired healing and chronic inflammatory conditions. We have discovered that VEGF contributes to resolution of macrophage-induced inflammation during wound healing and that it stimulates macrophage death. The studies proposed here are to test the possibility that VEGF is a player in resolution of inflammation and that LIGHT mediates the VEGF effects on resolution of inflammation. Because resolution of inflammation occurs poorly or not at all in most abnormal healing situations, this line of investigation is significant for heath because it identifies a potentially novel strategy for improving impaired healing, a critical medical area.

描述（由申请人提供）：炎症是正常伤口修复的关键过程。受伤后，细胞因子被激活并将白细胞（包括巨噬细胞）趋化至伤口部位。巨噬细胞是肉芽组织正确形成的关键，因为它们清除伤口中的死亡细胞并产生大量细胞因子，从而启动愈合组织的形成。虽然炎症早期涉及的许多详细机制是已知的，但涉及炎症消退的机制却知之甚少。了解炎症如何结束与了解炎症的开始同样重要，因为炎症的延长会导致愈合受损和慢性炎症。 VEGF 是伤口愈合的关键因素，主要因其在血管生成中的作用而闻名。然而，最近 VEGF 逐渐成为免疫和炎症的调节剂。我们发现 VEGF 有助于解决伤口愈合过程中巨噬细胞诱导的炎症，并刺激培养物中的巨噬细胞凋亡。我们还表明 VEGF 刺激人巨噬细胞中 TNFSF14/LIGHT 的表达。 LIGHT 是细胞因子 TNF 超家族的成员，已知可调节 T 细胞的共刺激以及粘膜肿瘤中的细胞凋亡。我们的研究结果指出了一种新的细胞因子调节途径参与炎症反应的解决。在此提出的工作中，我们探讨了 VEGF 在伤口愈合过程中炎症消退中新发现的功能的后果。我们假设 VEGF 在愈合过程中的一个新功能是调节受损组织中巨噬细胞的存活，而光是这一过程的关键介质。具体来说，我们将：（1）确定VEGF是否在体内诱导巨噬细胞凋亡并在愈合过程中刺激LIGHT表达；（2）确定VEGF诱导的巨噬细胞死亡与LIGHT之间的关系。我们将使用培养的人类巨噬细胞、正常小鼠和转基因小鼠的组合，以及 VEGF 和 LIGHT 依赖性途径的激动剂/拮抗剂。将使用组织化学和免疫学技术、ELISA、多重RT-PCR和siRNA技术。所提出的工作是新颖的，因为它揭示了 VEGF 以前未知的功能，而且它很重要，因为它可能促进针对愈合不良的伤口以及其他以过度炎症为特征的疾病和 VEGF 上调的肿瘤的新疗法的开发。由于在大多数异常愈合情况下，炎症的消退效果很差或根本没有消退，因此这一研究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，这是一个关键的医学领域。公共卫生相关性：炎症是正常伤口修复的关键过程。受伤后，细胞因子被激活并将白细胞（包括巨噬细胞）趋化至伤口部位。巨噬细胞是肉芽组织正确形成的关键，因为它们清除伤口中的死亡细胞并产生大量细胞因子，从而启动愈合组织的形成。了解炎症如何结束与了解其开始同样重要，因为炎症的延长会导致愈合受损和慢性炎症。我们发现 VEGF 有助于解决伤口愈合过程中巨噬细胞诱导的炎症，并刺激巨噬细胞死亡。这里提出的研究是为了测试 VEGF 在炎症消退中发挥作用以及光介导 VEGF 对炎症消退的影响的可能性。由于在大多数异常愈合情况下炎症的消退效果很差或根本没有消退，因此这一研究对健康具有重要意义，因为它确定了一种潜在的新策略来改善受损的愈合（这是一个关键的医学领域）。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deletion of a tumor necrosis superfamily gene in mice leads to impaired healing that mimics chronic wounds in humans.

DOI：
10.1111/j.1524-475x.2012.00785.x
发表时间：
2012-05
期刊：
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
影响因子：
0
作者：
Petreaca ML;Do D;Dhall S;McLelland D;Serafino A;Lyubovitsky J;Schiller N;Martins-Green MM
通讯作者：
Martins-Green MM

Insulin regulates multiple signaling pathways leading to monocyte/macrophage chemotaxis into the wound tissue.