Allergic inflammation is a complex disease that involves the trafficking and mobilization of multiple leukocytes, including eosinophils and T-cells, to sites of inflammation. Increased expression of Th2 cytokines, chemokines, vascular adhesion molecules and growth factors leading to exacerbation of the inflammatory response, including increased airway hyperactivity (AHR), airway remodeling and pulmonary angiogenesis are observed during airway allergic inflammation. Since eosinophils play an important role in the pathogenesis of allergic inflammation, in the last decade we have focused our attention on the mechanisms by which this cell type is generated, how it interacts with the vascular endothelium and how it is recruited to sites of inflammation. These studies have resulted in the identification of key molecules involved in the sequestration of eosinophils to different vascular beds such as the peritoneum and the pulmonary vascular bed. Our preliminary studies suggest that in addition to cell surface selectins and integrins, galectin- 3 (Gal-3), a carbohydrate-binding lectin that recognizes N-glycans expressed by MgatS, can (i) function as a novel vascular and cell adhesion molecule to support eosinophil trafficking, (ii) participate in the generation of Th2 cytokines and (iii) induce AHR in mice. In this competing continuation, we hypothesize that Gal-3 as well as N-glycans expressed by MgatS play an important role in the pathogenesis of acute and chronic airway allergic inflammation including asthma. To examine this, we have proposed three specific aims. In the first aim, using intravital microscopy, we will examine the function of Gal-3 as a novel adhesion molecule that supports cell adhesion by binding to multiple ligands, including N-glycans containing poly N- acetyllactosamine residues, VCAM-1 and alpha4 integrins, to support trafficking of eosinophils under conditions of flow in different vascular beds. In the next aim, using Gal-3-/- and Mgat-5-/- mice, we will determine the role of Gal-3 and Mgat5 in mediating immune responses including, AHR, expression of adhesion molecules and chemokines, Th1/Th2 cytokine release, mast cell activation and survival of inflammatory leukocytes during chronic allergic inflammation. Finally, based on our observation that Gal-3 is expressed in the airways and lung tissue associated with airway remodeling in chronically allergen-challenged mice, we propose to examine the mechanisms by which Gal-3 and its N-glycan-containing ligands expressed by MgatS promote airway remodeling and pulmonary angiogenesis associated with allergic inflammation utilizing Gal-3-/- and Mgat-5-/- mice. Overall, the proposed studies will delineate the importance of Gal-3 and its ligands in acute and chronic phases of airway allergic inflammation. Understanding the role of lectin-carbohydrate interactions in allergic inflammation has the potential to lead to the development of glycan-based therapies (or their mimetics) for the treatment of allergic diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI035796-13
Application #
7578391
Study Section
Special Emphasis Panel (ZRG1-III-F (01))
Program Officer
Sawyer, Richard T
Project Start
1995-06-01
Project End
2010-08-31
Budget Start
2007-09-19
Budget End
2008-08-31
Support Year
13
Fiscal Year
2007
Total Cost
$353,803
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Ge, Xiao Na; Ha, Sung Gil; Rao, Amrita et al. (2014) Endothelial and leukocyte heparan sulfates regulate the development of allergen-induced airway remodeling in a mouse model. Glycobiology 24:715-27
Ha, Sung Gil; Ge, Xiao Na; Bahaie, Nooshin S et al. (2013) ORMDL3 promotes eosinophil trafficking and activation via regulation of integrins and CD48. Nat Commun 4:2479
Kang, Bit Na; Ha, Sung Gil; Bahaie, Nooshin S et al. (2013) Regulation of serotonin-induced trafficking and migration of eosinophils. PLoS One 8:e54840
Ge, Xiao Na; Greenberg, Yana; Hosseinkhani, M Reza et al. (2013) High-fat diet promotes lung fibrosis and attenuates airway eosinophilia after exposure to cockroach allergen in mice. Exp Lung Res 39:365-78
Axelsson, Jakob; Xu, Ding; Kang, Bit Na et al. (2012) Inactivation of heparan sulfate 2-O-sulfotransferase accentuates neutrophil infiltration during acute inflammation in mice. Blood 120:1742-51
Kang, Bit Na; Ha, Sung Gil; Ge, Xiao Na et al. (2012) The p110? subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice. Am J Physiol Lung Cell Mol Physiol 302:L1179-91
Long, Chunmei; Hosseinkhani, M Reza; Wang, Yue et al. (2012) ADAM17 activation in circulating neutrophils following bacterial challenge impairs their recruitment. J Leukoc Biol 92:667-72
Bahaie, Nooshin S; Hosseinkhani, M Reza; Ge, Xiao Na et al. (2012) Regulation of eosinophil trafficking by SWAP-70 and its role in allergic airway inflammation. J Immunol 188:1479-90
Bahaie, Nooshin S; Kang, Bit Na; Frenzel, Elizabeth M et al. (2011) N-Glycans differentially regulate eosinophil and neutrophil recruitment during allergic airway inflammation. J Biol Chem 286:38231-41
Pandit, Terlika S; Hosseinkhani, M Reza; Kang, Bit Na et al. (2011) Chronic allergen challenge induces pulmonary extramedullary hematopoiesis. Exp Lung Res 37:279-90

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