While the goal of this project is to determine the contributions of EOS to airway inflammation and remodeling, airway eosinophilia is an important marker of asthma exacerbations, disease severity and response to corticosteroid therapy, the exact role that eosinophils (EOS) play in asthma remains to be established. Based upon current understanding of the function of EOS and our preliminary data, it is our hypothesis that EOS, through cell-cell interactions, enhance the production of cytokines by T cells and matrix proteins by fibroblasts to promote allergic airway inflammation and fibrogenesis. We also provide evidence that EOS contribute to airway inflammation by producing T cell active chemokines and enhancing! cell function via direct cellcell interaction, mediated by integrins. We provide evidence that EOS are the major source of transforming growth factor (TGF)-p in bronchial lavage (BAL) fluid and that they can augment the generation of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen III by human bronchial fibroblasts (Fb). Furthermore, we have observed a correlation between BAL EOS and the appearance of Fb-like cells in BAL fluid obtained after allergen challenge. Therefore, existing literature and our published, as well as preliminary data, provide strong support for our hypothesis and rationale for the proposed studies. To test the above hypothesis and establish the role of EOS in allergic airway inflammation and the initiation of fibrogenesis/remodeling, we propose the following specific aims: 1. To establish the contribution of EOS to allergic airway inflammation including the contribution of EOS-T cell integrin interactions to cytokine generation and the in vivo effect of EOS on allergic airway inflammation in asthma;and 2. To establish the contribution of EOS to the initiation of airway remodeling/fibrogenesis, with a focus on exploring the role of EOS-Fb integrin interactions in TGF-01 generation by EOS and production of ECM proteins by Fb, and testing the in vivo effect of EOS on the presence of TGF-pl and ECM proteins in patients with asthma. From these studies, it is expected that novel and improved understanding of the role of EOS in allergic inflammation and asthma will emerge providing rationale for new paradigms in the treatment of asthma and other eosinophitic disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL088594-04
Application #
8217347
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$466,324
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Esnault, Stephane; Torr, Elizabeth E; Bernau, Ksenija et al. (2017) Endogenous Semaphorin-7A Impedes Human Lung Fibroblast Differentiation. PLoS One 12:e0170207
Esnault, Stephane (2017) The neglected of eosinophil biology, IL-3 finds sustenance in the basophil. J Leukoc Biol 101:615-616
Esnault, Stephane; Bernau, Ksenija; Torr, Elizabeth E et al. (2017) RNA-sequencing analysis of lung primary fibroblast response to eosinophil-degranulation products predicts downstream effects on inflammation, tissue remodeling and lipid metabolism. Respir Res 18:188
Shen, Zhong-Jian; Hu, Jie; Kashi, Venkatesh P et al. (2017) Epstein-Barr Virus-induced Gene 2 Mediates Allergen-induced Leukocyte Migration into Airways. Am J Respir Crit Care Med 195:1576-1585
Johansson, M W; Khanna, M; Bortnov, V et al. (2017) IL-5-stimulated eosinophils adherent to periostin undergo stereotypic morphological changes and ADAM8-dependent migration. Clin Exp Allergy 47:1263-1274
Kelly, Elizabeth A; Esnault, Stephane; Liu, Lin Ying et al. (2017) Mepolizumab Attenuates Airway Eosinophil Numbers, but Not Their Functional Phenotype, in Asthma. Am J Respir Crit Care Med 196:1385-1395

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