Role of n3 PUFAs and inflammation-resolving lipid mediator, RvD1, in alcoholic liver disease

n3 PUFA 和炎症缓解脂质介质 RvD1 在酒精性肝病中的作用

• 批准号: 10625849
• 负责人: IRINA A. KIRPICH
• 金额: $ 31.49万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625849
• 关键词: Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Animal Model; Attenuated; Bacteria; Biological Response Modifiers; Chronic; Cytokine Signaling; Data; Development; Diet; Dietary Fats; Dietary Fatty Acid; Dietary Supplementation; Disease Progression; Down-Regulation; Effectiveness; Engineering; Ethanol; Experimental Animal Model; FAT gene; FDA approved; FPR2 gene; Functional disorder; Health; Heavy Drinking; Hepatic; Hepatocellular Damage; Homeostasis; Host Defense; Human; Immune; Immune response; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Intestinal permeability; Intestines; Kentucky; Linoleic Acids; Liver; Macrophage; Mediating; Mediator; Microbe; Modeling; Molecular; Mus; Nuclear; Nutritional; Organoids; Pathogenesis; Patients; Phagocytosis; Phenotype; Plants; Plasma; Play; Production; Prognosis; Research; Resolution; Rodent; Role; Sampling; Severities; Severity of illness; Signal Transduction; Survivors; Technology; Testing; Therapeutic Agents; Tissues; Transcript; Transgenic Organisms; Translating; Whole Blood; attenuation; cytokine; exosome; gut inflammation; gut-liver axis; improved; in vivo evaluation; intestinal barrier; lipid mediator; liver inflammation; liver injury; monocyte; nanoparticle; novel; novel therapeutic intervention; nutrition; organ injury; peripheral blood; preclinical study; receptor; repaired; systemic inflammatory response; therapeutic effectiveness; tissue repair

Alcoholic liver disease (ALD) is a major and increasing health problem in the US (especially in Kentucky) and worldwide. In spite of the magnitude of this problem, there is no FDA-approved therapy for any stage of ALD. In addition, the mechanisms and regulators of the disease progression and severity are not well understood. Dietary fats play an important interactive role with alcohol consumption in ALD pathogenesis, however, the role of n3 PUFAs in ALD are not well defined. Our central hypothesis is that n3 PUFAs are beneficial in ALD, in part, via n3-PUFA-derived pro-resolving mediators which facilitate inflammation resolution, improvement in the gut-liver axis, and subsequent attenuation of liver injury. We propose that resolvin D1 (RvD1) is a potent therapeutic agent in severe ALD acting via RvD1-FPR2-NEAT1 signaling to suppress pro-inflammatory cytokines and to promote repair of hepatocellular damage, in part, via enhancement of pro-restorative macrophages. We postulate that compromised inflammation resolution due to impaired RvD1 production/signaling is one of the critical nutritional contributing factors to the progressive ALD and severity of alcoholic hepatitis (AH) in humans. The Specific Aims of the proposal are: Aim 1. To test whether n3 PUFAs exert beneficial effects on EtOH- associated liver injury/inflammation by enhancing the effectiveness of inflammation resolution and by repair of hepatocellular damage through increase in n3-PUFA-derived specialized pro-resolving mediators promoting (SPMs), and RvD1-FPR2 and Neat1-mediated suppression of pro-inflammatory cytokine signaling and reprogramming pro-inflammatory macrophages into a pro-restorative phenotype. Wild Type (WT), Fpr2-/-, Neat1-/-, and transgenic fat-1 mice (which are able to endogenously convert n6 to n3 PUFAs) will be used in this Aim. We will also examine the therapeutic effectiveness of RvD1 utilizing a novel nanoparticle technology of targeted RvD1 delivery examine the role n3-PUFAs to the liver with plant-derived edible exosomes. Aim 2. To and RvD1 in maintaining gut barrier integrity, and in the resolution of intestinal inflammation in experimental ALD. We will: i) test in vivo, in animal models, and in vitro, in intestinal organoid culture, whether n3 PUFA or RvD1 improve intestinal barrier damage by attenuating intestinal immune dysregulation; ii) test in vivo whether disruption of the RvD1-FPR2 axis exacerbates, while blocking Neat1 signaling attenuates intestinal inflammation and alterations in the gut barrier integrity; iii) test a novel therapeutic strategy of administering an engineered bacteria strain to convert n6 to n3 PUFAs in the intestine and thus to attenuate gut barrier dysfunction in mice. In Aim 3, we seek to translate and extend our findings in animal models to human ALD. Utilizing de-identified human samples we will: i) determine effects of n3-PUFA dietary supplementation on plasma SPM levels, markers of liver injury, systemic inflammation, and intestinal permeability in heavy drinking individuals; ii) examine plasma SPM levels, and SPM synthesis in whole blood and peripheral blood monocytes (PBMCs) obtained from AH patients; and iii) test whether RvD1 improves phagocytosis/efferocytosis of PBMCs obtained from AH patients.

酒精性肝病（ALD）是美国（尤其是肯塔基州）的一个主要且日益严重的健康问题 全世界。尽管这个问题很严重，但 FDA 还没有批准针对 ALD 任何阶段的治疗方法。在 此外，疾病进展和严重程度的机制和调节因素尚不清楚。饮食 脂肪与饮酒在 ALD 发病机制中发挥着重要的相互作用作用，然而，n3 的作用 ALD 中的 PUFA 尚未明确定义。我们的中心假设是 n3 PUFA 对 ALD 有益，部分是通过 n3-PUFA 衍生的促消退介质，可促进炎症消退、改善肠道肝脏 轴，以及随后的肝损伤减弱。我们认为 resolvin D1 (RvD1) 是一种有效的治疗方法 严重 ALD 中的药物通过 RvD1-FPR2-NEAT1 信号传导抑制促炎细胞因子并 部分通过增强促恢复巨噬细胞来促进肝细胞损伤的修复。我们 假设 RvD1 产生/信号传导受损导致炎症消退受损是原因之一 人类进行性酒精性肝病（ALD）和酒精性肝炎（AH）严重程度的关键营养因素。 该提案的具体目标是： 目标 1. 测试 n3 PUFA 是否对 EtOH-发挥有益作用 通过增强炎症消退的有效性和通过 通过增加 n3-PUFA 衍生的专门促分解介质来修复肝细胞损伤 促进 (SPM)、RvD1-FPR2 和 Neat1 介导的促炎细胞因子信号传导抑制 将促炎巨噬细胞重新编程为促恢复表型。野生型 (WT)、Fpr2-/-、 Neat1-/- 和转基因 fat-1 小鼠（能够将 n6 内源性转化为 n3 PUFA）将用于此研究 目的。我们还将利用新型纳米颗粒技术检查 RvD1 的治疗效果 靶向 RvD1 递送检查 n3-PUFA 的作用 将植物来源的可食用外泌体输送到肝脏。目标 2. 至 RvD1 在维持肠道屏障完整性以及实验性 ALD 中肠道炎症的解决中发挥着重要作用。 我们将： i) 在动物模型中进行体内测试，以及在肠类器官培养中进行体外测试，无论是 n3 PUFA 还是 RvD1 通过减轻肠道免疫失调来改善肠道屏障损伤； ii) 体内测试是否 RvD1-FPR2 轴的破坏会加剧，而阻断 Neat1 信号传导则会减轻肠道炎症 以及肠道屏障完整性的改变； iii) 测试一种新的治疗策略，即施用工程化药物 细菌菌株在肠道中将 n6 转化为 n3 PUFA，从而减轻小鼠肠道屏障功能障碍。 在目标 3 中，我们寻求将我们在动物模型中的发现转化并扩展到人类 ALD。利用去识别化 人类样本我们将： i) 确定 n3-PUFA 膳食补充剂对血浆 SPM 水平、标记物的影响 酗酒者的肝损伤、全身炎症和肠道通透性； ii) 检查血浆 从 AH 获得的全血和外周血单核细胞 (PBMC) 中的 SPM 水平和 SPM 合成 患者; iii)测试RvD1是否改善从AH患者获得的PBMC的吞噬作用/胞吞作用。