A Critical Role for Leukotriene B4 in Lymphedema

白三烯 B4 在淋巴水肿中的关键作用

• 批准号: 10322667
• 负责人: Mark Robert Nicolls
• 金额: $ 49.72万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-21 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322667
• 关键词: Address; Affect; Antigen Presentation; Applications Grants; Arachidonate 5-Lipoxygenase; Back; Biology; Biophysics; Biopsy; Blood; Blood Circulation; Cancer Survivor; Cell Survival; Cells; Chronic; Clinical; Clinical Trials; Data; Dendritic Cells; Disease; Drug Targeting; Exposure to; Future; Genes; Genetic; Goals; Grant; Growth; Human; Immune; Immunity; Immunophenotyping; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Investigation; Leukotriene B4; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Capillaries; Lymphatic Endothelial Cells; Lymphatic function; Lymphedema; Mediating; Medical; Metabolism; Microcirculatory Bed; Molecular; Nature; Neuropilin-2; Paper; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Phenotype; Physiological; Property; Publishing; Pump; RNA; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Role; Sampling; Signal Pathway; Signal Transduction; Skin; Surveys; T-Cell Activation; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Toxic effect; Transcript; Ubenimex; Vascular Endothelial Growth Factor Receptor-3; Vascular remodeling; Work; cell growth; cell injury; curative treatments; design; effective therapy; efficacy testing; immunoregulation; in vivo; lipid mediator; lymphatic circulation; lymphatic pump; notch protein; pre-clinical; repaired; skin disorder; sphingosine 1-phosphate; synthetic enzyme; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; tumor-immune system interactions; ward

PROJECT SUMMARY / ABSTRACT Lymphedema is a chronic and debilitating condition currently without approved medical therapies. Recent investigations suggest a central role for inflammation in this disease. We discovered that leukotriene B4 (LTB4), a critical lipid mediator of inflammation, promotes lymphatic endothelial cell (LEC) sprouting and growth at low concentrations (10nM), and causes LEC injury at high concentrations (200nM) by differentially affecting two essential lymphatic survival pathways, VEGFR3 and Notch. During pre-clinical lymphedema progression, lymphatic fluid LTB4 concentrations rise from initial pro-lymphangiogenic concentrations, into an anti- lymphangiogenic range which may induce pathology. Anti-LTB4 therapy reverses pre-clinical lymphedema. This finding is the scientific basis for a Phase 2 clinical trial (ULTRA), which is currently testing the efficacy of LTB4-targeted therapy for lymphedema. New results from a separate proof-of-concept clinical trial are positive, making this the first effective medicinal therapy for this condition. Even though anti-LTB4 therapy may be helpful for lymphedema, it is likely not curative, and more information is needed to understand how inflammatory pathways promote disease. Studies proposed in the grant are designed to address fundamental mechanistic questions about how LTB4 damages lymphatic capillaries and promotes a proinflammatory microenvironment. Our global hypothesis is that after lymphatic injury, increased LTB4 exacerbates lymphedema by inhibiting key lymphatic growth pathways, interfering with the (blood) microvascular circulation, transforming LECs and redirecting the immune microenvironment. To address these issues, this proposal is divided into three Specific Aims as follows. Aim 1 is to study the mechanisms by which LTB4 alters pro-lymphangiogenic signaling pathways, causes blood vascular remodeling and changes LEC cellular identity. Aim 2 will investigate how LTB4 impacts the immune microenvironment in lymphedema by influencing the activation and phenotype of proinflammatory dendritic cells and T lymphocytes and by changing lymphatic immunoregulatory functions. Finally, Aim 3 will use omic technologies to evaluate clinical lymphedema samples collected by the ULTRA trial to assess the genetic networks built around LTB4 biology in lymphedema. The goals of these studies are to understand the molecular mechanisms of reparative lymphangiogenesis, the plasticity of LEC identify and the dynamics of immune regulation in lymphedema. By carefully assessing the immune microenvironment and the global transcriptome in lymphedema, it should be possible to evolve better drug therapies for this pervasive and, otherwise, unremitting condition.

项目概要/摘要 淋巴水肿是一种慢性且使人衰弱的疾病，目前尚无批准的药物治疗方法。最近的 研究表明炎症在这种疾病中起着核心作用。我们发现白三烯 B4 (LTB4)、 炎症的关键脂质介质，促进淋巴内皮细胞 (LEC) 在低水平下萌芽和生长 浓度（10nM），并在高浓度（200nM）时通过差异影响两个来引起 LEC 损伤 重要的淋巴存活途径、VEGFR3 和 Notch。在临床前淋巴水肿进展期间， 淋巴液 LTB4 浓度从最初的促淋巴管生成浓度上升到抗淋巴管生成浓度。 可能诱发病理的淋巴管生成范围。抗 LTB4 疗法可逆转临床前淋巴水肿。 这一发现是 2 期临床试验 (ULTRA) 的科学基础，该试验目前正在测试 LTB4 淋巴水肿靶向治疗。一项单独的概念验证临床试验的新结果是积极的， 使其成为治疗这种疾病的第一个有效的药物疗法。尽管抗 LTB4 疗法可能 对淋巴水肿有帮助，但可能无法治愈，需要更多信息来了解如何 炎症途径会促进疾病。拨款中提出的研究旨在解决基本问题 关于 LTB4 如何损害毛细淋巴管并促进促炎的机制问题 微环境。我们的总体假设是，淋巴损伤后，LTB4 增加会加剧 通过抑制关键淋巴生长途径、干扰（血液）微血管循环来治疗淋巴水肿， 转化 LEC 并重新调整免疫微环境。 为了解决这些问题，该提案分为以下三个具体目标。目标 1 是研究 LTB4 改变促淋巴管生成信号通路、导致血管重塑的机制 并改变 LEC 细胞身份。目标 2 将研究 LTB4 如何影响免疫微环境 通过影响促炎树突状细胞和 T 淋巴细胞的活化和表型来减轻淋巴水肿 并通过改变淋巴免疫调节功能。最后，Aim 3将使用omic技术来评估 ULTRA 试验收集的临床淋巴水肿样本用于评估围绕 LTB4 构建的遗传网络 淋巴水肿的生物学。 这些研究的目的是了解修复性淋巴管生成的分子机制， LEC 识别的可塑性和淋巴水肿免疫调节的动态。通过仔细评估 免疫微环境和淋巴水肿的整体转录组，应该有可能进化得更好 针对这种普遍存在且持续不断的病症的药物疗法。

项目成果

Exploring disease interrelationships in patients with lymphatic disorders: A single center retrospective experience.

• DOI: 10.1002/ctm2.760
• 发表时间: 2022-04
• 期刊: CLINICAL AND TRANSLATIONAL MEDICINE
• 影响因子: 10.6
• 作者: Rockson, Stanley G.;Zhou, Xin;Zhao, Lan;Hosseini, Davood K.;Jiang, Xinguo;Sweatt, Andrew J.;Kim, Dongeon;Tian, Wen;Snyder, Michael P.;Nicolls, Mark R.
• 通讯作者: Nicolls, Mark R.

Colorectal Cancer-Associated Microbiome Patterns and Signatures.

• DOI: 10.3389/fgene.2021.787176
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Zhao L;Cho WC;Nicolls MR
• 通讯作者: Nicolls MR

The Human Respiratory Microbiome: Current Understandings and Future Directions.

• DOI: 10.1165/rcmb.2022-0208tr
• 发表时间: 2023-03
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4

Severe Pulmonary Arterial Hypertension Is Characterized by Increased Neutrophil Elastase and Relative Elafin Deficiency.

• DOI: 10.1016/j.chest.2021.06.028
• 发表时间: 2021-10
• 期刊: Chest
• 影响因子: 9.6
• 作者: Sweatt AJ;Miyagawa K;Rhodes CJ;Taylor S;Del Rosario PA;Hsi A;Haddad F;Spiekerkoetter E;Bental-Roof M;Bland RD;Swietlik EM;Gräf S;Wilkins MR;Morrell NW;Nicolls MR;Rabinovitch M;Zamanian RT
• 通讯作者: Zamanian RT

Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation.

淋巴 S1P 信号异常会加剧淋巴功能障碍和组织炎症。

• DOI: 10.1101/2023.06.08.23291175
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Kim,Dongeon;Tian,Wen;Wu,TimothyTing-Hsuan;Xiang,Menglan;Vinh,Ryan;Chang,Jason;Gu,Shenbiao;Lee,Seunghee;Zhu,Yu;Guan,Torrey;Schneider,EmilieClaire;Bao,Evan;Dixon,JBrandon;Kao,Peter;Pan,Junliang;Rockson,StanleyG;Jiang,Xin
• 通讯作者: Jiang,Xin