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.
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.
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