Adherence of circulating eosinophils to the vascular endothelium and their accumulation at extravascular sites in inflamed tissues is a hallmark of allergic inflammation. However, the molecular mechanisms mediating eosinophil adhesion under conditions of flow in vivo are not well understood. Recent studies on neutrophils have shown that intravascular adhesion of these cells is a multi-step process involving distinct adhesion and activation steps. Adhesion molecules include members of the selectin family and beta2 integrins which promote neutrophil rolling and subsequent extravasation. We have recently observed that eosinophils from atopic patients similarly roll and adhere to IL-1 stimulated endothelial cells at shear rates. We have found that a beta1 integrin, VLA-4, in addition to L-selectin promotes early events of human eosinophil adhesion to endothelial cells in vivo.
The aim of the proposed research is to elucidate the functional role of adhesion receptors in mediating human eosinophil interaction with vascular adhesion molecules in vivo. Using intravital microscopy we will (1) examine the role of L-selectin and VLA-4 integrin in promoting human eosinophil rolling along IL-1 or IL-4 stimulated endothelial cells in vivo. Using anti-VLA-4 and L-selectin antibodies and cell lines transfected with cDNA for human VLA-4 we will determine if both receptors function sequentially or in parallel to promote eosinophil rolling; (2) determine the effects of eosinophil-active cytokines, IL-5 and GM-CSF, on receptor activation and in vivo adhesion of circulating eosinophils (3) examine the effect of chemokines, RANTES, GM- CSF and PAF on receptor mediated firm adhesion (sticking) and subsequent extravasation of normodense and hypodense subpopulations across cytokine stimulated mesenteric EC in vivo and (4) determine the role of histamine, GM-CSF, IL-1, IL-4 and IL-5 on expression of inducible vascular endothelial surface ligands and their role in promoting rolling, sticking and transendothelial migration of activated eosinophils at physiological shear rates in vivo. The surface expression of vascular adhesion molecules in the mesentery under conditions of flow will be correlated with the in vivo function of human eosinophils. These proposed studies are intended to give a better understanding of molecular mechanisms mediating cell adhesion and provide a basis for examining therapeutic strategies for the treatment of allergic inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI035796-03
Application #
2429417
Study Section
Pathology A Study Section (PTHA)
Project Start
1995-06-01
Project End
2000-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
3
Fiscal Year
1997
Total Cost
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
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
Ge, Xiao Na; Bahaie, Nooshin S; Kang, Bit Na et al. (2010) Allergen-induced airway remodeling is impaired in galectin-3-deficient mice. J Immunol 185:1205-14

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