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.

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 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 ainway inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL024136-34
Application #
8451350
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
34
Fiscal Year
2013
Total Cost
$312,646
Indirect Cost
$109,534
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Ma, Qiaoli; Dieterich, Lothar C; Ikenberg, Kristian et al. (2018) Unexpected contribution of lymphatic vessels to promotion of distant metastatic tumor spread. Sci Adv 4:eaat4758
Kim, Minah; Nitschké, Maximilian; Sennino, Barbara et al. (2018) Amplification of Oncolytic Vaccinia Virus Widespread Tumor Cell Killing by Sunitinib through Multiple Mechanisms. Cancer Res 78:922-937
Nitschké, Maximilian; Bell, Alexander; Karaman, Sinem et al. (2017) Retrograde Lymph Flow Leads to Chylothorax in Transgenic Mice with Lymphatic Malformations. Am J Pathol 187:1984-1997
Shepherd, Joanna; Fisher, Matthew; Welford, Abigail et al. (2017) The protective role of sphingosine-1-phosphate against the action of the vascular disrupting agent combretastatin A-4 3-O-phosphate. Oncotarget 8:95648-95661
Baluk, Peter; Yao, Li-Chin; Flores, Julio C et al. (2017) Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract. JCI Insight 2:
Pinkard, Henry; Corbin, Kaitlin; Krummel, Matthew F (2016) Spatiotemporal Rank Filtering Improves Image Quality Compared to Frame Averaging in 2-Photon Laser Scanning Microscopy. PLoS One 11:e0150430
Sen, Debasish; Jones, Stephen M; Oswald, Erin M et al. (2016) Tracking the Spatial and Functional Gradient of Monocyte-To-Macrophage Differentiation in Inflamed Lung. PLoS One 11:e0165064
Greenland, John R; Wong, Charissa M; Ahuja, Rahul et al. (2016) Donor-Reactive Regulatory T Cell Frequency Increases During Acute Cellular Rejection of Lung Allografts. Transplantation 100:2090-8
Huang, Jennifer L; Woolf, Adrian S; Kolatsi-Joannou, Maria et al. (2016) Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases. J Am Soc Nephrol 27:69-77
Caughey, George H (2016) Mast cell proteases as pharmacological targets. Eur J Pharmacol 778:44-55

Showing the most recent 10 out of 593 publications