The goal of this project is to examine the interactions between eosinophils and adhesive extracellular proteins occurring during transit of eosinophils from blood stream to airway and learn how the interactions relate to the alteration of eosinophil phenotype. We hypothesize that a vicious cycle may develop that contributes to asthma whereby eosinophilic infiltration causes deposition of abnormal extracellular matrix that in turn causes more infiltration and functional upregulation of eosinophils.
The specific aims of this proposal are to: (A) develop models of adhesion and migration of eosinophils with an emphasis on cell function; (B) determine that distribution of relevant matrix proteins in the models vis-a-vis normal, non-asthmatic allergic and asthmatic bronchial mucosa; (C) determine the role of integrins in models established in specific aim A; (D) determine the role of cytokines and chemokines in eosinophil-matrix interactions; and (E) test whether products of activated eosinophils alter deposition of extracellular matrix in cultures of lung fibroblasts. To accomplish these goals, peripheral blood eosinophils will be studied in tow-and three-dimensional systems of cell adhesion, spreading, and migration. The production of superoxide anion, leukotriene C4, and cytokines, e.g., GM-DSF, extent of degranulation, and cellular survival will be assessed to determine alteration of cell function after various incubations with adhesive endothelial cell (VCAM-1) and matrix proteins (fibronectin, laminin isoforms). The effects of cytokines, chemokines, and antiintegrin antibodies will be examined in these assays to identify key interactions that could occur within the tissue. Expression of adhesive proteins in asthmatic airways will be determined by immunocytochemistry and in situ hybridization or reverse transcription-PCR. Projects of activated eosinophils will be tested for their ability to cause increased deposition of matrix proteins as occurs in airways of asthmatics. Changes in phenotype of blood eosinophils that result from these in vitro conditions will be compared to similar assessments on eosinophils from airways of patients with asthma to correlate biological and clinical relevance. These observations should provide new insights into eosinophil biology and mechanisms of persistent airway damage in asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
1P50HL056396-02
Application #
6273182
Study Section
Project Start
1997-12-01
Project End
1998-11-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Kelly, Elizabeth A; Esnault, Stephane; Johnson, Sean H et al. (2016) Human eosinophil activin A synthesis and mRNA stabilization are induced by the combination of IL-3 plus TNF. Immunol Cell Biol 94:701-8
Lee, Yong Gyu; Jeong, Jong Jin; Nyenhuis, Sharmilee et al. (2015) Recruited alveolar macrophages, in response to airway epithelial-derived monocyte chemoattractant protein 1/CCl2, regulate airway inflammation and remodeling in allergic asthma. Am J Respir Cell Mol Biol 52:772-84
Park, Gye Young; Lee, Yong Gyu; Berdyshev, Evgeny et al. (2013) Autotaxin production of lysophosphatidic acid mediates allergic asthmatic inflammation. Am J Respir Crit Care Med 188:928-40
Sorkness, Ronald L; Szakaly, Renee J; Rosenthal, Louis A et al. (2013) Viral bronchiolitis in young rats causes small airway lesions that correlate with reduced lung function. Am J Respir Cell Mol Biol 49:808-13
Denlinger, Loren C; Kelly, Elizabeth A B; Dodge, Ann M et al. (2013) Safety of and cellular response to segmental bronchoprovocation in allergic asthma. PLoS One 8:e51963
Gavala, M L; Kelly, E A B; Esnault, S et al. (2013) Segmental allergen challenge enhances chitinase activity and levels of CCL18 in mild atopic asthma. Clin Exp Allergy 43:187-97
Oh, Jiyoung; Malter, James S (2013) Pin1-FADD interactions regulate Fas-mediated apoptosis in activated eosinophils. J Immunol 190:4937-45
Ochkur, Sergei I; Kim, John Dongil; Protheroe, Cheryl A et al. (2012) A sensitive high throughput ELISA for human eosinophil peroxidase: a specific assay to quantify eosinophil degranulation from patient-derived sources. J Immunol Methods 384:10-20
Curran, Colleen S; Bertics, Paul J (2012) Lactoferrin regulates an axis involving CD11b and CD49d integrins and the chemokines MIP-1? and MCP-1 in GM-CSF-treated human primary eosinophils. J Interferon Cytokine Res 32:450-61
Kelly, Elizabeth A B; Liu, Lin Ying; Esnault, Stephane et al. (2012) Potent synergistic effect of IL-3 and TNF on matrix metalloproteinase 9 generation by human eosinophils. Cytokine 58:199-206

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