Lymphatic Dysfunction in the Pathogenesis of COPD

慢性阻塞性肺病发病机制中的淋巴功能障碍

• 批准号: 10590330
• 负责人: Hasina Outtz Reed
• 金额: $ 71.1万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590330
• 关键词: Address; Affect; Automobile Driving; Biology; Blood; Cause of Death; Cells; Chronic Obstructive Pulmonary Disease; Coagulation Process; Data; Disease; Disease Progression; Event; FDA approved; Genetic; Goals; Hospitalization; Human; Immune; Immunohistochemistry; Immunology; Impairment; Individual; Inflammation; Inflammatory Response; Injury; Journals; Knowledge; Link; Liquid substance; Lung; Lymph; Lymphatic; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphatic function; Maps; Measures; Mediating; Modeling; Molecular; Mus; PAR-1 Receptor; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Proteomics; Publishing; Pulmonary Emphysema; Pulmonary Inflammation; Reporting; Role; Severity of illness; Signal Transduction; Structure of parenchyma of lung; Techniques; Testing; Therapeutic; Thrombin; Thrombin Receptor; Thromboplastin; Thrombosis; Time; Tissues; United States; Up-Regulation; Work; cell injury; cigarette smoke; cigarette smoke-induced; cigarette smoke-induced lung injury; clinical investigation; clinically relevant; endothelial dysfunction; experience; exposure to cigarette smoke; in vitro activity; in vivo; inflammatory lung disease; inflammatory milieu; inhibitor; lung injury; lymph flow; lymphatic drainage; lymphatic dysfunction; lymphatic vessel; mouse model; novel; pharmacologic; pulmonary function; response; single-cell RNA sequencing; symptomatic improvement; targeted agent; thrombotic; tool; transcriptome sequencing

Project Summary/Abstract Chronic Obstructive Pulmonary Disease (COPD) is a destructive inflammatory lung disease that is the 4th leading cause of death in the U.S., killing more than 150,000 people yearly. Current therapies can improve symptoms and reduce hospitalization, but none modify this disease or stop its relentless progression. COPD is commonly caused by cigarette smoke (CS), but we do not yet fully understand the early events that trigger inflammation and tissue destruction that could be intervened upon to halt the cycle of lung injury. This knowledge gap has led to an absence of disease-modifying therapies and a therapeutic pipeline that has thus far led to only incremental advances on existing drugs. The lymphatic vessels are uniquely positioned to regulate inflammatory responses in most tissues because they drain fluid and traffic immune cells in the form of lymph. We have recently published our findings that impaired lymphatic drainage alone is sufficient to induce lung inflammation that culminates in the hallmarks of human COPD. Furthermore, we have discovered that lymphatic endothelial cell injury and lymphatic vessel thrombosis are early events after CS exposure. Interestingly, we not only identified lung lymphatic thrombosis in human lung tissue from patients with COPD, we also found that the degree of lymphatic thrombosis is linked to COPD severity. This work suggests that lymphatic dysfunction may be central to COPD pathogenesis but the role of the lymphatics in CS-induced lung injury and inflammation is not well understood. Filling this critical knowledge gap promises to result in new classes of lymphatic-targeted agents that have the potential to block or reverse COPD and lead to prolonged survival in these patients. We will investigate the novel concept that lymphatic dysfunction is a defining early event in the pathogenesis of emphysema that can contribute to progressive tissue destruction. Therefore, the objective of this proposal is to define the actionable mechanisms that result in lymphatic endotheliopathy after CS exposure and drive progression of COPD. Our central hypothesis is that lymphatic thrombosis due to CS drives disease progression through activation of thrombin in the lymphatic endothelium. Our approach consists of lymphatic- specific manipulation of the coagulation pathway and thrombin signaling in order to mechanistically address the consequences of lymphatic thrombosis on disease progression in a murine model of COPD (Aim 1), and the mechanism by which CS causes lymphatic dysfunction (Aim 2). Furthermore, we will use these models to test how inhibition of thrombin activity or specific inhibition of the thrombin receptor affects the inflammatory response to CS and disease progression. When completed, these studies will lead to a shift in the current paradigm for the pathogenesis of COPD to include early changes in lung lymphatic function. In doing so, we will both broaden the field and set the stage for further studies with immediate clinical relevance given the use of existing therapies to target lymphatic function.

项目总结/摘要 慢性阻塞性肺疾病（COPD）是一种破坏性的炎症性肺部疾病， 在美国的死因，每年造成超过15万人死亡目前的治疗方法可以改善症状 减少住院治疗，但没有一个能改变这种疾病或阻止其无情的发展。COPD通常 吸烟引起的炎症，但我们还没有完全了解引发炎症的早期事件 和组织破坏，可以通过干预来阻止肺损伤的循环。这种知识差距导致 到目前为止，疾病修饰疗法和治疗管道的缺乏只导致增量 现有药物的进展。淋巴管的独特定位是调节炎症反应 在大多数组织中，因为它们以淋巴液的形式排出液体和运输免疫细胞。我们最近出版了 我们的研究发现，淋巴引流受损本身就足以引起肺部炎症， 人类慢性阻塞性肺病的特征此外，我们发现淋巴管内皮细胞损伤和 淋巴管血栓形成是CS暴露后的早期事件。有趣的是，我们不仅发现了肺 在COPD患者的人肺组织中，我们还发现淋巴结血栓形成的程度 血栓形成与COPD严重程度有关。这项工作表明淋巴功能障碍可能是COPD的核心 发病机制，但在CS诱导的肺损伤和炎症中的作用还没有得到很好的理解。 填补这一关键的知识空白，有望产生新的一类靶向药物， 可能阻断或逆转COPD，并延长这些患者的生存期。我们会调查这部小说 淋巴功能障碍是肺气肿发病机制中的决定性早期事件， 会导致组织的不断破坏因此，本提案的目的是界定 CS暴露和驱动后导致淋巴管内皮病的可行机制 COPD的进展。我们的中心假设是CS引起的淋巴血栓形成是疾病的驱动力 通过激活淋巴管内皮中的凝血酶而进展。我们的方法包括淋巴- 凝血途径和凝血酶信号传导的特异性操纵，以便机械地解决 淋巴血栓形成对COPD小鼠模型疾病进展的影响（目的1），以及 CS引起淋巴功能障碍的机制（目的2）。此外，我们将使用这些模型来测试 凝血酶活性的抑制或凝血酶受体的特异性抑制如何影响炎症反应 CS和疾病进展。这些研究完成后，将导致目前的模式发生转变， COPD的发病机制包括肺淋巴功能的早期变化。这样一来，我们双方都将扩大 该领域，并为进一步研究奠定基础，考虑到现有疗法的使用， 针对淋巴功能。