Adherence of circulating eosinophil to vascular endothelium and their recruitment to extravascular sites in inflamed tissues is the hallmark of allergic inflammation. Recent studies have identified an important role for adhesion molecules and other mediators in the sequestration of eosinophils to sites of inflammation. In this competing renewal we first postulate that vascular cell adhesion molecule (VCAM-1) is a multifunctional cell adhesion molecule that supports initial rolling, activation dependent stable adhesion and chemokine mediated transmigration of eosinophils by interacting with different activation states of alpha4 integrins. Using VCAM-1 deficient heterozygous mice we will determine the tissue specific contribution of VCAM-1 to eosinophil recruitment to sites of allergic inflammation in the skin and peritoneum. Our studies have identified that CD44 may function as a novel rolling receptor for human eosinophils. Furthermore, C3a appears to function as a eosinophil active chemoattractant to mediate stable adhesion of rolling cells. We will therefore, examine the function of CD44 and C3a in eosinophil mediated allergic inflammation. Since matrix matalloproteinases (MMPs) play an important role in the migration of leukocytes within the extravascular space, we will examine the importance of eosinophil expressed MMP-9 as well as an inducible eosinophil-specific MMP, designated as MMP-E, in mediating eosinophil chemotaxis in vivo as part of the second specific aim. In addition monoclonal antibodies against MMP-E will be generated with a view to better understand the biochemical and functional regulation of MMP-E in the context of eosinophil recruitment and allergic inflammation. Since exposure to cytokines such as IL-5 leads to significant eosinophilia, in the third specific aim, the mechanisms of IL-5/allergen-induced mobilization of hematopoietic progenitor/stem cell (HPSC) and eosinophil committed progenitors in the bone marrow will be investigated. We will also investigate how IL-5 modulates the trafficking/migration of HPSC from the bone marrow microenvironment (stromal and endothelial cells) to distal sites of allergic inflammation (lung endothelial cells under conditions of flow. Using in vivo techniques of intravital microscopy along with in vitro molecular and cellular tools, the proposed studies are intended to give a better understanding of the molecular mechanisms mediating eosinophil interactions in inflamed blood vessels and tissues and to provide a basis for developing novel therapeutic strategies for treatment of allergic inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI035796-10
Application #
6757228
Study Section
Pathology A Study Section (PTHA)
Program Officer
Sawyer, Richard T
Project Start
1995-06-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2006-05-31
Support Year
10
Fiscal Year
2004
Total Cost
$414,600
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
941462285
City
San Diego
State
CA
Country
United States
Zip Code
92121
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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