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.
| Moon, Hyung-Geun; Kim, Seung-Jae; Jeong, Jong Jin et al. (2018) Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitization. Immunity 49:275-287.e5 |
| Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83 |
| Johansson, Mats W; Kelly, Elizabeth A; Nguyen, Christopher L et al. (2018) Characterization of Siglec-8 Expression on Lavage Cells after Segmental Lung Allergen Challenge. Int Arch Allergy Immunol 177:16-28 |
| Evans, Michael D; Esnault, Stephane; Denlinger, Loren C et al. (2018) Sputum cell IL-1 receptor expression level is a marker of airway neutrophilia and airflow obstruction in asthmatic patients. J Allergy Clin Immunol 142:415-423 |
| Esnault, Stephane; Hebert, Alexander S; Jarjour, Nizar N et al. (2018) Proteomic and Phosphoproteomic Changes Induced by Prolonged Activation of Human Eosinophils with IL-3. J Proteome Res 17:2102-2111 |
| Bortnov, Valeriu; Annis, Douglas S; Fogerty, Frances J et al. (2018) Myeloid-derived growth factor is a resident endoplasmic reticulum protein. J Biol Chem 293:13166-13175 |
| Schwantes, Elizabeth A; Evans, Michael D; Cuskey, Alex et al. (2018) Elevated fractional exhaled nitric oxide and blood eosinophil counts are associated with a 17q21 asthma risk allele in adult subjects. J Asthma Allergy 11:1-9 |
| Tomasini-Johansson, Bianca R; Mosher, Deane F (2018) Microtiter assays for quantitation of assembly of plasma and cellular fibronectin. Methods Cell Biol 143:157-170 |
| Turton, Keren B; Wilkerson, Emily M; Hebert, Alex S et al. (2018) Expression of novel ""LOCGEF"" isoforms of ARHGEF18 in eosinophils. J Leukoc Biol 104:135-145 |
| Bernau, Ksenija; Leet, Jonathan P; Esnault, Stephane et al. (2018) Eosinophil-degranulation products drive a proinflammatory fibroblast phenotype. J Allergy Clin Immunol 142:1360-1363.e3 |
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