Lymphangiogenesis and Angiogenesis in Airway Inflammation

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气道炎症的病理生理，并可作为治疗靶点。淋巴管排出液体，作为适应性免疫传入肢体的一部分，作为抗原和免疫细胞从气道转运到淋巴结的途径。血管作为血浆泄漏和白细胞流入炎症血管的守门人，调节着天然和适应性免疫反应的大小。Aim #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，持续的气道炎症导致粘膜淋巴异常，损害液体排泄，并可能导致支气管淋巴水肿，从而恶化气道阻塞，并通过改变液体/细胞外渗和清除的正常平衡扰乱免疫反应。提出的实验将确定促进淋巴重塑的因素，确定

This project will examine the mechanisms, consequences, and reversibility of lymphangiogenesis and angiogenesis in chronic ainway 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 ain/vays, regulate the magnitude of native and adaptive immune responses. The goal of Aim #1 is to define the abnormalities of lymphatic vessels in chronic ainway 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 ainway 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 ainway 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 ainway 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 ainway function and for developing strategies to ameliorate airway inflammation by reversing the vascular changes.