The Pulmonary Lymphatics in Inflammation and Disease

项目总结/摘要 肺淋巴管被认为是肺功能的关键，因为肺对炎症的易感性。 水肿和不断暴露于病原体。事实上，异常的肺动脉高压见于 与几乎所有慢性肺部疾病相关，包括移植排斥、肺纤维化和 肺气肿，这两种疾病加起来影响了近3200万美国人。然而，目前尚不清楚这些 淋巴功能异常是疾病的后果，或者如果淋巴功能障碍是致病性的， 潜在的治疗目标尚未探索。这一建议既解决了我们在学习能力方面的一个突出差距， 肺淋巴功能，并探讨了在肺部疾病中的基本作用，使用两种新的 肺淋巴流受损的小鼠模型。第一个模型使用Clec 2-β突变小鼠， 由于淋巴结静脉交界处缺乏血小板栓和逆行流动导致淋巴流量严重受损 血液进入淋巴系统，阻止淋巴引流。在第二个模型中，肺特异性淋巴细胞 通过诱导白喉毒素介导的小鼠肺淋巴管内皮细胞的细胞死亡来实现缺失 移植这些模型表明，淋巴功能障碍导致白细胞的积累和形成 肺实质中的淋巴组织。值得注意的是，淋巴流受损的小鼠也有肺泡炎。 类似于人类肺气肿的扩大和肺损伤。在本提案的目标1中，两种模式都将 用于研究肺毛细血管在白细胞运输中的作用，并检测淋巴功能是否 在免疫细胞特化和肺的炎症环境中起作用。Aim 2将使用肺 功能测试、CT成像和表达研究，以检验淋巴功能障碍导致淋巴结转移的假设。 自发性肺气肿表型的小鼠，并将研究淋巴功能障碍的机制， 会导致肺损伤。这些研究预计将提供体内模型， 淋巴功能、炎症和肺损伤之间的相互作用，并可能揭示一个未被认识到的作用 治疗肺气肿的药物该提案还在职业发展计划中发挥着核心作用， 一位成功的独立研究者，专注于血管生物学和疾病。此处描述的培训计划 提供了一个机会，获得在人类疾病，转录组学和生理小鼠建模的专业知识， 和小鼠肺的放射线照相分析。宾夕法尼亚大学是一个理想的环境， 执行这一培训计划不仅是因为其优良的物质资源，而且还因为其智力 研究人员社区，具有早期研究人员的强大指导记录。

PROJECT SUMMARY/ABSTRACT Pulmonary lymphatic vessels are thought to be critical for lung function due to the vulnerability of the lungs to edema and their constant exposure to pathogens. Indeed, abnormal pulmonary lymphatics are seen in association with nearly every chronic lung disease including transplant rejection, pulmonary fibrosis, and emphysema, which combined affect nearly 32 million Americans. However, it remains unclear whether these abnormal lymphatics are a consequence of the disease or if lymphatic dysfunction is pathogenic, leaving potential therapeutic targets unexplored. This proposal addresses both an outstanding gap in our ability to study pulmonary lymphatic function and also investigates the basic role of lymphatics in lung disease using two novel mouse models of impaired pulmonary lymphatic flow. The first model uses Clec2-­mutant mice, which have severely impaired lymph flow due to an absent platelet plug at the lympho-­venous junction and retrograde flow of blood into the lymphatic system that prevents lymphatic drainage. In the second model, lung-­specific lymphatic deletion is achieved by inducing diphtheria toxin-­mediated cell death of lymphatic endothelial cells in mouse lung transplants. These models show that lymphatic dysfunction leads to accumulation of leukocytes and formation of lymphoid tissue in the lung parenchyma. Significantly, mice with impaired lymphatic flow also have alveolar enlargement and lung injury that resembles human emphysema. In Aim 1 of this proposal, both models will be used to investigate the role of pulmonary lymphatics in leukocyte trafficking and test whether lymphatic function plays a role in immune cell specification and the inflammatory milieu of the lung. Aim 2 will use pulmonary function tests, CT imaging, and expression studies to test the hypothesis that lymphatic dysfunction causes a spontaneous emphysema phenotype in mice, and will investigate the mechanism by which lymphatic dysfunction causes lung injury using rescue studies. These studies are predicted to provide in vivo models for understanding the interplay between lymphatic function, inflammation, and lung injury and may uncover an unappreciated role for lymphatics in emphysema. This proposal also plays a central role in a career development plan for becoming a successful independent investigator focused on vascular biology and disease. The training plan described here provides an opportunity to gain expertise in mouse modeling of human disease, transcriptomics, and physiologic and radiographic analysis of the mouse lung. The University of Pennsylvania is an ideal environment in which to execute this training plan not only because of its excellent physical resources, but also because of its intellectual community of researchers with a track record of strong mentorship of early stage investigators.