Lymphatic Dysfunction in the Pathogenesis of COPD

项目摘要/摘要 慢性阻塞性肺疾病(COPD)是一种破坏性的炎症性肺疾病，居第四位 死因在美国，每年造成超过15万人死亡。目前的治疗方法可以改善症状 并减少住院，但都不能改变这种疾病或阻止其无情的发展。慢性阻塞性肺疾病通常 由香烟烟雾(CS)引起，但我们还不完全了解引发炎症的早期事件 以及可以干预的组织破坏，以阻止肺损伤的循环。这种知识鸿沟导致了 由于缺乏疾病修正疗法和治疗管道，到目前为止只导致了增量 现有药物的进展。淋巴管是调节炎症反应的独特位置。 在大多数组织中，因为它们以淋巴的形式排出液体和运输免疫细胞。我们最近发表了 我们的研究发现，仅淋巴引流受损就足以引发肺部炎症，最终导致 人类慢性阻塞性肺病的特征。此外，我们还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，我们不仅发现了肺部 从COPD患者肺组织中淋巴管血栓形成情况来看，我们还发现淋巴管的程度 血栓形成与COPD的严重程度有关。这项工作表明淋巴功能障碍可能是慢性阻塞性肺疾病的核心 但淋巴管在CS诱导的肺损伤和炎症中的作用尚不清楚。 填补这一关键的知识空白有望产生新的淋巴靶向药物，这些药物具有 有可能阻断或逆转COPD，并延长这些患者的生存时间。我们将调查这部小说 淋巴功能障碍是肺气肿发病机制中一个决定性的早期事件，它可以 有助于渐进性组织破坏。因此，这项提案的目的是界定 CS暴露和驱动后导致淋巴管内皮病变的可操作机制 慢性阻塞性肺疾病的进展。我们的中心假设是CS导致的淋巴管血栓导致疾病 通过激活淋巴管内皮细胞中的凝血酶而进展。我们的方法包括淋巴- 凝血途径和凝血酶信号的特定操作，以机械地解决 淋巴管血栓形成对COPD小鼠模型疾病进展的影响(目标1)，以及 CS导致淋巴功能障碍的机制(目标2)。此外，我们将使用这些模型来测试 凝血酶活性抑制或凝血酶受体特异性抑制如何影响炎症反应 与CS和疾病进展有关。当这些研究完成后，将导致当前范式的转变 COPD的发病机制包括早期肺淋巴功能的改变。通过这样做，我们都将扩大 鉴于现有疗法的使用，这一领域并为具有直接临床意义的进一步研究奠定了基础 以淋巴功能为目标。

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.