Pro-resolving lipid mediators in immunity and vascular biology

免疫和血管生物学中的促溶解脂质介质

• 批准号: 10220112
• 负责人: Matthew R Spite
• 金额: $ 52.46万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220112
• 关键词: Acute; Adhesions; Agonist; Anti-Inflammatory Agents; Biology; Blood Vessels; Cardiovascular Diseases; Cells; Chemotaxis; Chronic; Clinical; Complication; Diabetic mouse; Diet; Disease; Dopamine D2 Receptor; Ear; Edema; Epidemic; Epithelial; Fibrosis; Functional disorder; GPR18 receptor; Genetic; Genetic Transcription; Glucose; Health; Host Defense; Immune; Immunity; Immunosuppression; Impaired wound healing; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interruption; Lead; Leukocytes; LoxP-flanked allele; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic clearance; Lymphatic function; Lymphedema; Mediating; Mediator of activation protein; Metabolic Diseases; Metabolism; Mus; Myeloid Cells; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Normal tissue morphology; Obese Mice; Obesity; Pathway interactions; Phagocytes; Phenotype; Play; Process; Production; Research; Resolution; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Source; Stress; Testing; Therapeutic; Time; Tissues; Wound models; acute wound; base; cell type; cellular targeting; chronic inflammatory disease; cytokine; diabetic ulcer; draining lymph node; healing; immune clearance; improved; in vivo; injured; knock-down; lipid mediator; lymphatic dysfunction; lymphatic vessel; macrophage; migration; novel; novel strategies; novel therapeutic intervention; programs; receptor; reparative process; response to injury; skin wound; tissue injury; tissue repair; transcriptome sequencing; wound; wound closure; wound healing

Project Summary/Abstract Impaired wound healing is a prominent clinical manifestation of chronic inflammatory diseases, such as obesity and type 2 diabetes (T2D). Acute wounds in individuals with T2D can become chronic and this is associated with sustained accumulation of pro-inflammatory leukocytes, prolonged edema, and fibrosis, leading to impaired wound closure (i.e. re-epithelialization). Functional lymphatic vessels are required for clearance of immune cells, edema, and host-defense, and several lines of evidence indicate that lymphatic clearance mechanisms are impaired in obesity and T2D. However, there are no current strategies to resolve inflammation, improve lymphatic function, and rescue defective tissue repair in obesity and T2D. In health, the acute inflammatory response that occurs during tissue injury is actively resolved, setting the stage for tissue repair. Pro-resolving lipid mediators, such as the resolvins, are critical mediators of active resolution of inflammation in part because they blunt inflammatory cytokine production and stimulate macrophage-mediated clearance of dead cells. We recently found that resolvins are generated in skin wounds and hasten tissue repair. Moreover, in work in progress, we discovered that specific receptors for resolvins are expressed on both macrophages and lymphatic vessels in skin wounds and that resolvin D2 (RvD2) reduces wound edema. Based on these exciting findings, we hypothesize that RvD2 engages its receptor on macrophages and lymphatic endothelial cells (LEC) to orchestrate clearance mechanisms during resolution to facilitate tissue repair. To this end, we propose to elucidate the role of RvD2 and its receptor in resolution of inflammation and edema during wound healing and determine the relative contribution of macrophages and LEC to this process by selectively deleting the RvD2 receptor in each cell type in vivo. We will uncover the mechanisms whereby RvD2 and its receptor regulate functions of macrophages and LEC important for resolution and edema clearance, and whether these processes can be rescued by RvD2 in obese-diabetic mice. Successful completion of these studies will uncover completely new roles of RvD2 and its receptor in macrophage and lymphatic function and could inform novel agonist-based approaches to rescue defective tissue repair in obesity and T2D, as well as other chronic inflammatory diseases.

项目摘要/摘要 伤口愈合受损是慢性炎症性疾病的突出临床表现，例如 肥胖和2型糖尿病（T2D）。 T2D患者的急性伤口可能会变得慢性，这是 与促炎性白细胞，长时间水肿和纤维化的持续积累相关， 导致伤口闭合受损（即再上皮化）。需要功能性淋巴管 免疫细胞，水肿和宿主防御的清除率以及几条证据表明淋巴 清除机制在肥胖和T2D中受到损害。但是，目前没有解决的策略 炎症，改善淋巴功能以及肥胖和T2D中的组织修复有缺陷的组织修复。在健康方面 在组织损伤期间发生的急性炎症反应被积极解决，为组织奠定了基础 维修。促分解脂质介质（例如分辨率）是主动分辨率的关键介体 炎症部分是因为它们钝化了炎症性细胞因子的产生并刺激巨噬细胞介导 清除死细胞。最近，我们发现在皮肤伤口中产生了分离剂并加速组织 维修。此外，在进行的工作中，我们发现了分辨素的特定受体。 巨噬细胞和皮肤伤口中的淋巴管和溶解D2（RVD2）都减少了伤口水肿。 根据这些令人兴奋的发现，我们假设RVD2在巨噬细胞和 淋巴内皮细胞（LEC）在分辨率期间协调清除机制以促进组织 维修。为此，我们建议阐明RVD2及其受体在解决炎症和受体中的作用 伤口愈合过程中的水肿并确定巨噬细胞和LEC对此过程的相对贡献 通过在体内选择性删除每个细胞类型中的RVD2受体。我们将发现该机制 RVD2及其受体调节巨噬细胞的功能，而LEC对于分辨率和水肿很重要 清除率，以及这些过程是否可以通过肥胖糖尿病小鼠中的RVD2营救。成功的 这些研究的完成将发现RVD2及其受体在巨噬细胞中的全新作用 淋巴功能，可以告知基于新型激动剂的方法来挽救缺陷的组织修复 肥胖和T2D以及其他慢性炎症性疾病。