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

基本信息

批准号：
10424510
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
项目类别：
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/10424510
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 regeneration tissue repair transcriptome sequencing wound wound closure wound healing

项目摘要

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.

项目概要/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成慢性伤口，这是与促炎性白细胞的持续积累、长期水肿和纤维化有关，导致伤口闭合受损（即上皮再生）。需要功能性淋巴管免疫细胞的清除、水肿和宿主防御，以及一些证据表明，淋巴管肥胖和 T2D 的清除机制受损。但目前尚无解决策略炎症，改善淋巴功能，并挽救肥胖和 T2D 的缺陷组织修复。在健康方面，组织损伤期间发生的急性炎症反应得到积极解决，为组织损伤奠定了基础维修。促溶解脂质介质，例如溶解素，是主动溶解脂质的关键介质。炎症的部分原因是它们削弱炎症细胞因子的产生并刺激巨噬细胞介导的清除死亡细胞。我们最近发现皮肤伤口中会产生分解素并加速组织维修。此外，在正在进行的工作中，我们发现解析素的特异性受体表达于皮肤伤口中的巨噬细胞和淋巴管，resolvin D2 (RvD2) 可减少伤口水肿。基于这些令人兴奋的发现，我们假设 RvD2 与其巨噬细胞上的受体结合，淋巴内皮细胞 (LEC) 在分解过程中协调清除机制以促进组织维修。为此，我们建议阐明 RvD2 及其受体在炎症和炎症消退中的作用。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选择性地删除体内每种细胞类型中的 RvD2 受体。我们将揭示其中的机制 RvD2 及其受体调节巨噬细胞和 LEC 的功能，对消退和水肿很重要清除，以及这些过程是否可以通过 RvD2 在肥胖糖尿病小鼠中挽救。成功的这些研究的完成将揭示 RvD2 及其受体在巨噬细胞和淋巴功能，并可以为基于激动剂的新方法提供拯救缺陷组织修复的新方法肥胖和 T2D，以及其他慢性炎症性疾病。