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.
Lymphatic vessels and blood vessels, as gatekeepers for entry and clearance of fluid and cells in tissues, play key roles in inflammatory ainway disease. Lymphatics and blood vessels proliferate and change in sustained inflammation, and their abnormalities contribute to mucosal edema and ainway 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.
|Greenland, J R; Jewell, N P; Gottschall, M et al. (2014) Bronchoalveolar lavage cell immunophenotyping facilitates diagnosis of lung allograft rejection. Am J Transplant 14:831-40|
|Baluk, Peter; Adams, Alicia; Phillips, Keeley et al. (2014) Preferential lymphatic growth in bronchus-associated lymphoid tissue in sustained lung inflammation. Am J Pathol 184:1577-92|
|Sutherland, Rachel E; Barry, Sophia S; Olsen, Joanna S et al. (2014) Dipeptidyl peptidase I controls survival from Klebsiella pneumoniae lung infection by processing surfactant protein D. Biochem Biophys Res Commun 450:818-23|
|Gérard, Audrey; Patino-Lopez, Genaro; Beemiller, Peter et al. (2014) Detection of rare antigen-presenting cells through T cell-intrinsic meandering motility, mediated by Myo1g. Cell 158:492-505|
|Ortiz-Muñoz, Guadalupe; Mallavia, Beñat; Bins, Adriaan et al. (2014) Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. Blood 124:2625-34|
|Giannotta, Monica; Benedetti, Sara; Tedesco, Francesco Saverio et al. (2014) Targeting endothelial junctional adhesion molecule-A/ EPAC/ Rap-1 axis as a novel strategy to increase stem cell engraftment in dystrophic muscles. EMBO Mol Med 6:239-58|
|Broz, Miranda L; Binnewies, Mikhail; Boldajipour, Bijan et al. (2014) Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26:638-52|
|Patnode, Michael L; Bando, Jennifer K; Krummel, Matthew F et al. (2014) Leukotriene B4 amplifies eosinophil accumulation in response to nematodes. J Exp Med 211:1281-8|
|Baluk, Peter; Phillips, Keeley; Yao, Li-Chin et al. (2014) Neutrophil dependence of vascular remodeling after Mycoplasma infection of mouse airways. Am J Pathol 184:1877-89|
|Lelkes, Efrat; Headley, Mark B; Thornton, Emily E et al. (2014) The spatiotemporal cellular dynamics of lung immunity. Trends Immunol 35:379-86|
Showing the most recent 10 out of 544 publications