Role(s) of VEGF in Resolution of Inflammation

VEGF 在炎症消退中的作用

• 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
• 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

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。在创伤后，细胞因子被激活并将白细胞（包括巨噬细胞）化学吸引到创伤部位。巨噬细胞是肉芽组织正确形成的关键，因为它们清理伤口中的死细胞并产生过多的细胞因子，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，但对炎症消退涉及的机制知之甚少。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。VEGF是伤口愈合中的关键因子，并且主要已知其在血管生成中的作用。然而，最近VEGF作为免疫和炎症的调节剂出现。我们已经发现VEGF有助于在伤口愈合期间巨噬细胞诱导的炎症的消退，并且它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TNFSF 14/LIGHT的表达。LIGHT是已知调节T细胞共刺激以及粘膜肿瘤中细胞凋亡的细胞因子TNF超家族的成员。我们的研究结果指出了一种新的尼古丁调节途径参与炎症反应的决议。在这里提出的工作中，我们解决了这些新发现的VEGF功能在伤口愈合过程中炎症消退的后果。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的巨噬细胞存活，而LIGHT是这一过程的关键介质。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在愈合过程中刺激LIGHT表达和（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巨噬细胞，正常和基因修饰的小鼠，加上VEGF和LIGHT依赖性途径的激动剂/拮抗剂的组合。将采用组织化学和免疫学技术、ELISA、多重RT-PCR和siRNA技术。这项工作是新颖的，因为它揭示了VEGF以前未知的功能，它是重要的，因为它可能有助于开发新的治疗方法，用于治疗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。由于在大多数异常愈合情况下，炎症的消退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。在创伤后，细胞因子被激活并将白细胞（包括巨噬细胞）化学吸引到创伤部位。巨噬细胞是肉芽组织正确形成的关键，因为它们清理伤口中的死细胞并产生过多的细胞因子，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。我们已经发现，VEGF有助于在伤口愈合期间解决巨噬细胞诱导的炎症，并且它刺激巨噬细胞死亡。这里提出的研究是为了测试VEGF是炎症消退中的参与者以及LIGHT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潜在新策略，这是一个关键的医学领域。

项目成果

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

小鼠肿瘤坏死基因的缺失导致愈合受损，该愈合模仿了人类的慢性伤口。

• 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
• 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.

• DOI: 10.1242/bio.026187
• 发表时间: 2018-01-17
• 期刊: Biology open
• 影响因子: 2.4
• 作者: Liu Y;Dhall S;Castro A;Chan A;Alamat R;Martins-Green M
• 通讯作者: Martins-Green M