The goal of this grant continues to be the elucidation of the mechanisms of inflammation in allergic diseases of the airways and the mechanisms by which glucocorticoids ameliorate allergic disease. Based upon recent findings in the laboratory, we have advanced three important hypotheses that will be tested by work described in this proposal. The first hypothesis is that direct inhibition of STAT6 in epithelial cells will produce anti-inflammatory effects that exceed or supplement those of glucocorticoids. Epithelial expression of STAT6-dependent genes is a centrally important event in allergic inflammation, and recent studies indicate that glucocorticoids have no direct effect on STAT6 signaling in epithelial cells. Experiments are proposed which will develop new methodologies to inhibit STAT6 in airway epithelial cells to test this hypothesis. The second hypothesis is that airway epithelial cells manifest a local equivalent of the acute phase response following stimulation with ligands for Toll-like receptors (TLR) and inflammatory cytokines. Increased expression of complement proteins, pentraxins, collectin molecules and other acute phase reactants by epithelium may participate in an active host defense response. Integrated microarray, gene ontology-based, analytical and functional studies will characterize the innate host defense molecules expressed by activated epithelial cells. Whether epithelial cells exert this response in vivo will be tested in normal human subjects and those with inflammatory diseases of the upper airways. The third hypothesis is that glucocorticoids inhibit inflammatory responses but spare, or even enhance, innate immune responses. Preliminary results and published literature support this hypothesis, which will be tested using a systematic analysis of glucocorticoid regulation of gene expression. Parallel studies will test the hypothesis that epithelial activation by TLR ligands, cytokines and glucocorticoids involves the CCAAT-enhancer binding protein (C/EBP) family of transcription factors. Whether glucocorticoids enhance the expression of innate host defense molecules will be tested in vivo in human subjects using well-established techniques to collect and analyze airway epithelial responses. The studies described in this proposal are likely to be of great relevance to the clinical use of glucocorticoids and may identify new strategies to develop drugs that will supplant or supplement glucocorticoids in the management of allergic disease of the airways.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068546-25
Application #
7448531
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
1983-09-20
Project End
2009-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
25
Fiscal Year
2008
Total Cost
$371,537
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Ogasawara, Noriko; Poposki, Julie A; Klingler, Aiko I et al. (2018) IL-10, TGF-?, and glucocorticoid prevent the production of type 2 cytokines in human group 2 innate lymphoid cells. J Allergy Clin Immunol 141:1147-1151.e8
Weibman, Ava R; Huang, Julia He; Stevens, Whitney W et al. (2017) A prospective analysis evaluating tissue biopsy location and its clinical relevance in chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol 7:1058-1064
Min, Jin-Young; Ocampo, Christopher J; Stevens, Whitney W et al. (2017) Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase. J Allergy Clin Immunol 139:130-141.e11
Min, Jin-Young; Nayak, Jayakar V; Hulse, Kathryn E et al. (2017) Evidence for altered levels of IgD in the nasal airway mucosa of patients with chronic rhinosinusitis. J Allergy Clin Immunol 140:1562-1571.e5
Lavin, Jennifer; Min, Jin-Young; Lidder, Alcina K et al. (2017) Superior turbinate eosinophilia correlates with olfactory deficit in chronic rhinosinusitis patients. Laryngoscope 127:2210-2218
Lidder, Alcina K; Detwiller, Kara Y; Price, Caroline P E et al. (2017) Evaluating metrics of responsiveness using patient-reported outcome measures in chronic rhinosinusitis. Int Forum Allergy Rhinol 7:128-134
Van Roey, Griet A; Vanison, Christopher C; Wu, Jeffanie et al. (2017) Classical complement pathway activation in the nasal tissue of patients with chronic rhinosinusitis. J Allergy Clin Immunol 140:89-100.e2
Schleimer, Robert P (2017) Immunopathogenesis of Chronic Rhinosinusitis and Nasal Polyposis. Annu Rev Pathol 12:331-357
Thompson, Christopher F; Price, Caroline P E; Huang, Julia He et al. (2016) A pilot study of symptom profiles from a polyp vs an eosinophilic-based classification of chronic rhinosinusitis. Int Forum Allergy Rhinol 6:500-7
Mahdavinia, Mahboobeh; Hsu, Joy; Norton, James E et al. (2015) Association of common filaggrin null mutations with atopy but not chronic rhinosinusitis. Ann Allergy Asthma Immunol 114:420-421

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