Neuroprotectins and Maresins for Macrophages in Diabetic Wound Healing

糖尿病伤口愈合中巨噬细胞的神经保护素和 Maresins

• 批准号: 8053910
• 负责人: Song Hong
• 金额: $ 29.49万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053910
• 关键词: American; Anabolism; Apoptosis; Autacoids; Complement; Complications of Diabetes Mellitus; Diabetes Mellitus; Diabetic mouse; Docosahexaenoic Acids; Endothelial Cells; F2-Isoprostanes; Fourier Transform; Generations; Glucose; Goals; Healed; Hyperglycemia; Impaired wound healing; Impairment; In Vitro; Kinetics; Lipids; Maps; Mass Spectrum Analysis; Mediator of activation protein; Medical; Modality; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Play; Process; Recovery; Research; Role; Simulate; Site; Skin; Supplementation; Testing; Time; Vascularization; Wound Healing; angiogenesis; base; cell motility; cytokine; diabetic; diabetic wound healing; healing; in vivo; insight; knockout gene; lipid mediator; macrophage; non-diabetic; novel; novel therapeutics; public health relevance; tandem mass spectrometry; tool; wound

DESCRIPTION (provided by applicant): Many Americans suffer from the non-healing wound complications associated with diabetes. The goal of this project is to elucidate the mechanisms of action of endogenous pro-healing lipid autacoids of macrophages (PLAM), which we discovered recently, in diabetic impairments of wound healing. These PLAMs include neuroprotectins (NPDs) and maresins, PLAMs are autacoids acting on the site of their biosynthesis. Macrophages (Mf) play critical roles in wound healing. In our preliminary studies, we show that healthy murine Mf and skin after wounding generate NPD1, maresin-1, and other novel lipid mediators. In contrast, the levels of these PLAMs are diminished in comparable Mf and wounds of diabetic mice. Wound PLAM levels are inversely correlated with the levels of the oxidative stress marker F4-neuroprostane, an autooxidized derivative of DHA. Moreover, we show that hyperglycemia diminishes PLAM formation by Mf of diabetic mice. We also show that treating Mf of diabetic mice with these PLAMs rescue Mf pro-healing functions in wounds of diabetic mice. These novel findings led to our following hypotheses: 1) Diabetic complications diminish the formation of PLAMs required for normal wound healing; 2) Supplementation with these PLAMs rescues the pro-healing function of diabetes-impaired macrophages on wounds and angiogenesis. We will test our hypotheses using a wound healing model of murine gene-knockout type II diabetes, Mf depletion, vascularization assessments in vivo and in vitro, and analysis via tandem mass spectrometry (MS), including Fourier transform FTMS. The Specific Aims are: Aim 1. Test the predictions about PLAM formation and its relationship with Mf and diabetic hyperglycemia and oxidative stress during wound healing. We will study wounds and Mf using our targeted LC-UV-MS/MS based mediator-lipidomic analysis to test the prediction that: 1A. the levels of F2-isoprostanes and F4-neuroprostanes representing diabetic oxidative-stress are temporally and inversely correlated with the diminished PLAM formation in wounds of diabetic mice. 1B. simulated hyperglycemia diminishes PLAM formation by Mf. 1C. Mf depletion significantly reduces the PLAM formation in wounds of non-diabetic mice. Aim 2. Test that supplementation of neuroprotectins, maresins, or novel PLAMs rescues diabetes-impaired Mf functions that promote wound healing. We will apply diabetic mouse-produced Mf treated with these PLAMs to wounds of diabetic mice to establish their actions. Aim 3. Test that supplementation with PLAMs rescues diabetes-impaired Mf functions that promote wound-healing-required angiogenesis in hyperglycemia. We will treat diabetes-impaired Mf with PLAMs under high-glucose conditions to determine if PLAMs can rescue Mf in promoting crucial angiogenic processes of wound healing. Completion of this proposed research will contribute to revealing the molecular and cellular mechanisms for novel endogenous lipid autacoids necessary to rescue diabetes-impaired macrophage functions vital to wound healing, and provide new insight for developing novel therapeutic modalities for treating wounds in diabetics. PUBLIC HEALTH RELEVANCE: The proposed research will define the mechanisms that supplementation of maresins, neuroprotectins, and candidates of novel pro-healing lipid autacoids and paracoids rescues diabetes-impaired macrophages, which enhance the healing in diabetes-impaired wounds. These mechanisms may be potential targets for developing therapeutical strategies to cure the nonhealing of diabetes-impaired wounds.

描述（由申请人提供）：许多美国人患有与糖尿病相关的无法愈合的伤口并发症。该项目的目标是阐明巨噬细胞内源性促愈合脂质自体物质 (PLAM) 在糖尿病伤口愈合损伤中的作用机制，我们最近发现了这种物质。这些 PLAM 包括神经保护素 (NPD) 和 maresins，PLAM 是作用于其生物合成位点的自体激素。巨噬细胞（Mf）在伤口愈合中发挥着关键作用。在我们的初步研究中，我们表明健康的小鼠 Mf 和受伤后的皮肤会产生 NPD1、maresin-1 和其他新型脂质介质。相比之下，在糖尿病小鼠的可比较的 Mf 和伤口中，这些 PLAM 的水平有所降低。伤口 PLAM 水平与氧化应激标记物 F4-神经前列腺素（DHA 的自氧化衍生物）的水平呈负相关。此外，我们发现高血糖会减少糖尿病小鼠 Mf 的 PLAM 形成。我们还表明，用这些 PLAM 治疗糖尿病小鼠的 Mf 可以挽救糖尿病小鼠伤口中的 Mf 促愈合功能。这些新发现引出了我们以下假设：1）糖尿病并发症减少了正常伤口愈合所需的 PLAM 的形成； 2) 补充这些PLAM可以挽救糖尿病受损的巨噬细胞对伤口和血管生成的促愈合功能。 我们将使用小鼠基因敲除 II 型糖尿病的伤口愈合模型、Mf 耗竭、体内和体外血管化评估以及通过串联质谱 (MS)（包括傅里叶变换 FTMS）进行分析来测试我们的假设。 具体目标是： 目标 1. 测试有关 PLAM 形成及其与 Mf 和糖尿病高血糖以及伤口愈合过程中氧化应激的关系的预测。我们将使用基于 LC-UV-MS/MS 的靶向介质脂质组学分析来研究伤口和 Mf，以测试以下预测：1A。代表糖尿病氧化应激的 F2-异前列腺素和 F4-神经前列腺素水平与糖尿病小鼠伤口中 PLAM 形成的减少呈时间负相关。 1B.模拟高血糖会减少 Mf 的 PLAM 形成。 1C. Mf 消耗显着减少非糖尿病小鼠伤口中 PLAM 的形成。目标 2. 测试补充神经保护素、maresins 或新型 PLAM 是否可以挽救糖尿病受损的促进伤口愈合的 Mf 功能。我们将用这些 PLAM 处理的糖尿病小鼠产生的 Mf 应用于糖尿病小鼠的伤口，以建立其作用。目标 3. 测试补充 PLAM 是否可以挽救糖尿病受损的 Mf 功能，从而促进高血糖情况下伤口愈合所需的血管生成。我们将在高血糖条件下用 PLAM 治疗糖尿病受损的 Mf，以确定 PLAM 是否可以拯救 Mf，促进伤口愈合的关键血管生成过程。 这项拟议研究的完成将有助于揭示新型内源性脂质自体物质的分子和细胞机制，以挽救对伤口愈合至关重要的糖尿病受损的巨噬细胞功能，并为开发治疗糖尿病伤口的新型治疗方式提供新的见解。 公共健康相关性：拟议的研究将确定补充 maresins、神经保护素以及新型促愈合脂质自体激素和类固醇候选物可拯救糖尿病受损的巨噬细胞，从而增强糖尿病受损伤口的愈合的机制。这些机制可能是开发治疗策略的潜在目标，以治愈糖尿病损伤的不愈合伤口。