Role(s) of VEGF in Resolution of Inflammation

VEGF 在炎症消退中的作用

• 批准号: 7740319
• 负责人: MANUELA M. MARTINS-GREEN
• 金额: $ 18.61万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740319
• 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

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，趋化的白细胞（包括巨噬细胞）到伤口部位。巨噬细胞是肉芽组织正确形成的关键，因为它们清理了伤口中的死细胞并产生大量的细胞因子，这些细胞因子启动了愈合组织的形成。尽管已知许多涉及的详细机制，但涉及炎症解决方案的机制知之甚少。了解炎症的结局与理解其开始一样重要，因为炎症的延长会导致愈合和慢性炎症状况受损。 VEGF是伤口愈合的关键因素，主要以其在血管生成中的作用而闻名。但是，最近VEGF成为免疫和炎症的调节剂。我们发现，VEGF有助于解决巨噬细胞诱发的伤口愈合过程中的炎症，并刺激培养物中的巨噬细胞凋亡。我们还表明，VEGF刺激人类巨噬细胞中TNFSF14/光的表达。 Light是已知的细胞因子TNF超家族的成员，这些细胞因子已知可调节T细胞的共刺激以及粘膜肿瘤中的凋亡。我们的发现指出了一种新型的细胞因子调节途径，涉及炎症反应的分辨率。在这里提出的工作中，我们解决了VEGF在伤口愈合过程中炎症解决这些新发现的功能的后果。我们假设VEGF在愈合过程中的新功能是对受损组织中巨噬细胞存活的调节，而光是该过程的关键介体。具体而言，我们将：（1）确定VEGF是否在体内诱导巨噬细胞凋亡并刺激愈合过程中的光表达，（2）确定VEGF诱导的巨噬细胞死亡与光之间的关系。我们将结合培养的人类巨噬细胞，正常和遗传改性的小鼠，再加上VEGF和光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。提出的这项工作是新颖的，因为它揭示了VEGF的先前未知功能，这一点很重要，因为它可能有助于开发用于治疗性较差的伤口的新疗法，以及其他以过度炎症和VEGF上调的肿瘤为特征的其他疾病。由于在大多数异常愈合情况下，炎症的分辨率都很差或根本不变，因此这种调查对健康非常重要，因为它确定了改善受损愈合受损的新策略，即关键的医疗领域。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，趋化的白细胞（包括巨噬细胞）到伤口部位。巨噬细胞是肉芽组织正确形成的关键，因为它们清理了伤口中的死细胞并产生大量的细胞因子，这些细胞因子启动了愈合组织的形成。了解炎症的结局与理解其开始一样重要，因为炎症的延长会导致愈合和慢性炎症状况受损。我们发现，VEGF有助于解决巨噬细胞诱导的伤口愈合过程中的炎症，并刺激巨噬细胞死亡。这里提出的研究是为了测试VEGF是炎症解决方案的可能性，并且光介导了VEGF对炎症解决方案的影响。由于在大多数异常愈合情况下，炎症的分辨率都很少或根本不变，因此这种调查对于荒地来说是重要的，因为它确定了改善受损愈合受损的潜在新型策略，即关键的医疗领域。