Pro-resolving lipid mediators in immunity and vascular biology

项目概要/摘要 伤口愈合受损是慢性炎性疾病的突出临床表现，例如 肥胖和2型糖尿病（T2 D）。患有T2 D的个体中的急性伤口可以变成慢性，这是 与促炎性白细胞的持续积累、长期水肿和纤维化相关， 导致受损的伤口闭合（即上皮再形成）。需要功能性淋巴管 免疫细胞的清除、水肿和宿主防御，以及几条证据表明淋巴细胞 清除机制在肥胖症和T2 D中受损。但是，目前没有解决的战略 炎症，改善淋巴功能，并挽救肥胖和T2 D中有缺陷组织修复。在健康方面， 在组织损伤期间发生的急性炎症反应被积极地解决，为组织 修复.促消退脂质介质，如消退素，是主动消退的关键介质。 炎症部分是因为它们减弱了炎性细胞因子的产生并刺激巨噬细胞介导的 清除死细胞。我们最近发现，消退素产生于皮肤伤口， 修复.此外，在进行中的工作中，我们发现，在细胞表面表达了消退素的特异性受体。 巨噬细胞和淋巴管，并且消退素D2（RvD 2）减少伤口水肿。 基于这些令人兴奋的发现，我们假设RvD 2与巨噬细胞上的受体结合， 淋巴管内皮细胞（LEC）在消退期间协调清除机制， 修复.为此，我们建议阐明RvD 2及其受体在炎症消退中的作用， 水肿在伤口愈合过程中，并确定相对贡献的巨噬细胞和LEC这一进程 通过在体内选择性地删除每种细胞类型中的RvD 2受体。我们将揭示 RvD 2及其受体调节巨噬细胞和LEC的功能，对消退和水肿至关重要 清除，以及这些过程是否可以通过RvD 2在肥胖糖尿病小鼠中挽救。成功 这些研究的完成将揭示RvD 2及其受体在巨噬细胞中的全新作用， 淋巴功能，并可以告知新的激动剂为基础的方法，以挽救有缺陷的组织修复， 肥胖症和T2 D，以及其他慢性炎症性疾病。

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.