Pro-resolving lipid mediators in immunity and vascular biology

项目摘要/摘要 创面愈合障碍是慢性炎症性疾病的显著临床表现，如 肥胖与2型糖尿病(T2D)患有T2D的人的急性伤口可以变成慢性的，这是 伴随着促炎白细胞的持续堆积，长期的浮肿和纤维化， 导致伤口闭合受损(即再上皮化)。需要有功能的淋巴管 免疫细胞的清除，水肿和宿主防御，以及几条证据表明淋巴管 在肥胖和T2D中，清除机制受损。然而，目前还没有解决这个问题的策略 发炎，改善淋巴功能，挽救肥胖和T2D的缺陷组织修复。在健康方面， 在组织损伤过程中发生的急性炎症反应被主动化解，为组织奠定了基础 修理。促拆分脂质介体，如分解素，是主动拆分的关键介体 炎症的部分原因是它们钝化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，分解素在皮肤伤口中产生，并加速组织 修理。此外，在进行中的工作中，我们发现解析素的特定受体在 皮肤伤口中有巨噬细胞和淋巴管，而解决素D2(RvD2)可减轻伤口水肿。 基于这些令人兴奋的发现，我们假设RvD2与巨噬细胞和 淋巴内皮细胞(LEC)在分解过程中协调清除机制以促进组织 修理。为此，我们建议阐明RvD2及其受体在消退炎症和 伤口愈合过程中的水肿并确定巨噬细胞和LEC在这一过程中的相对贡献 通过在体内选择性地删除每种细胞类型的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至关重要 清除，以及这些过程是否可以被RvD2拯救肥胖-糖尿病小鼠。成功 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，并可提供新的激动剂为基础的方法，以挽救缺陷组织修复 肥胖和T2D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.