Lymphangiogenesis and Angiogenesis in Airway Inflammation

描述(申请人提供)：本项目将研究慢性呼吸道炎症中淋巴管生成和血管生成的机制、后果和可逆性。总的假设是，粘膜淋巴管和血管的异常以多种方式参与了呼吸道炎症的病理生理学，并可作为治疗的靶点。淋巴管排出液体，作为获得性免疫的传入肢体的一部分，充当抗原和免疫细胞从呼吸道到淋巴结转移的途径。血管作为血浆渗漏和白细胞流入炎症呼吸道的守门人，调节着天然和获得性免疫反应的大小。目标1的目标是定义慢性呼吸道炎症中淋巴管的异常，确定驱动因素，并确定这些变化的后果和可逆性。我们的假设是，持续的呼吸道炎症会导致粘膜淋巴管的异常，损害液体的排出，并可能导致支气管淋巴水肿，从而通过改变液体/细胞外渗和清除的正常平衡来加重气道阻塞和扰乱免疫反应。拟议的实验将确定促进淋巴重塑的因素，确定导致初始淋巴管内皮连接缺陷的条件，并探索异常的可逆性。目标2的目的是确定血管生成和血管重塑在呼吸道炎症中的机制、后果和可逆性。我们的假设是，白细胞募集趋化因子与促炎细胞因子和局部血管生成因子协同作用，推动内皮细胞重塑，从而有利于呼吸道炎症的特征渗漏和白细胞内流。拟议的实验将确定趋化因子和细胞因子的数量、细胞来源和作用，这些因子和细胞因子介导白细胞的流入和生长、淋巴管和血管的重塑和功能可塑性。肺支原体感染或长时间抗原攻击后慢性呼吸道炎症的小鼠模型将与具有条件性功能获得或功能丧失突变的基因改变小鼠的变化进行比较。假定的介体和可逆性的贡献将通过使用功能阻断抗体、可溶性诱骗受体和受体酪氨酸激酶抑制剂来确定。总之，这些研究将提供一个概念性框架，用于确定淋巴管和血管的变化如何有助于组织重塑和气道功能改变，并为制定通过逆转血管变化来缓解气道炎症的策略提供一个概念性框架。公共卫生相关性：淋巴管和血管作为组织中液体和细胞进入和清除的守门人，在炎症性呼吸道疾病中发挥关键作用。淋巴管和血管在持续性炎症中增殖和改变，它们的异常通过增加渗漏和损害液体清除而导致粘膜水肿和呼吸道功能障碍。通过阐明这些血管变化的机制、后果和可逆性，该项目将促进对使用改建的淋巴管和血管作为呼吸道炎症治疗靶点所需的理解。

DESCRIPTION (provided by applicant): This project will examine the mechanisms, consequences, and reversibility of lymphangiogenesis and angiogenesis in chronic airway inflammation. The overall hypothesis is that abnormalities in mucosal lymphatics and blood vessels contribute in multiple ways to the pathophysiology of airway inflammation and can be exploited as therapeutic targets. Lymphatics drain fluid and, as part of the afferent limb of adaptive immunity, serve as routes for antigen and immune cell transit from airways to lymph nodes. Blood vessels, as gatekeepers for plasma leakage and leukocyte influx into inflamed airways, regulate the magnitude of native and adaptive immune responses. The goal of Aim #1 is to define the abnormalities of lymphatic vessels in chronic airway inflammation, identify the driving factors, and determine the consequences and reversibility of the changes. Our hypothesis is that persistent airway inflammation leads to abnormalities in mucosal lymphatics that impair fluid drainage, and could lead to bronchial lymphedema, which worsens airway obstruction and perturbs immune responses by altering the normal balance of fluid/cell extravasation and clearance. Proposed experiments will identify factors that promote lymphatic remodeling, determine conditions that lead to defective endothelial junctions in initial lymphatics, and explore the reversibility of the abnormalities. The goal of Aim #2 is to determine the mechanism, consequences, and reversibility of angiogenesis and blood vessel remodeling in airway inflammation. Our hypothesis is that leukocyte-recruiting chemokines, acting in concert with proinflammatory cytokines and local angiogenic factors, drive endothelial cell remodeling that favors leakiness and leukocyte influx characteristic of airway inflammation. Proposed experiments will determine the amounts, cellular sources, and actions of chemokines and cytokines that mediate leukocyte influx and growth, remodeling, and functional plasticity of lymphatics and blood vessels. Mouse models of chronic airway inflammation after Mycoplasma pulmonis infection or prolonged antigen challenge will be compared to changes in genetically altered mice that have conditional gain-of-function or loss-of-function mutations. The contribution of putative mediators and reversibility will be determined through the use of function-blocking antibodies, soluble decoy receptors, and receptor tyrosine kinase inhibitors. Together, the studies will provide a conceptual framework for determining how changes in lymphatics and blood vessels contribute to tissue remodeling and altered airway function and for developing strategies to ameliorate airway inflammation by reversing the vascular changes. PUBLIC HEALTH RELEVANCE: Lymphatic vessels and blood vessels, as gatekeepers for entry and clearance of fluid and cells in tissues, play key roles in inflammatory airway disease. Lymphatics and blood vessels proliferate and change in sustained inflammation, and their abnormalities contribute to mucosal edema and airway dysfunction by increasing leakage and impairing fluid clearance. By elucidating the mechanisms, consequences, and reversibility of these vascular changes, the project will advance the understanding needed to use remodeled lymphatics and blood vessels as therapeutic targets in airway inflammation.