This project will contribute to the overall objectives of this AADC by focusing on the contribution of sinusitis to the presence and severity of asthma. Sinusitis and asthma are very common conditions characterized by a similar inflammatory infiltrate, but the relationship between them is poorly understood. We have shown that extensive mucosal disease is a major independent risk factor for asthma. This finding could indicate that either the two conditions have a common cause or that one is dependent on the other. We will distinguish these possibilities by performing a prospective study on the relationship between sinusitis and asthma. Inherent in these studies is the critical need to develop and validate a methodology for objectively measuring the presence, severity, and clinical course of chronic hyperplastic sinusitis (CHS)/nasal polyposis (NP). As a disease of hyperplastic mucosal tissue with eosinophilia, we will show that the hyperplasia will be readily visualized and accurately quantified by CT scan. We will gain insights into the pathophysiology and interplay of these conditions by identifying changes in the nose and sinuses that correlate with increased inflammation in the lungs during experimental RV infection and nasal allergen challenges. Our proposed mechanism by which RV infection and allergen contribute to inflammation of the sinuses and lungs is that T cells primed in the nares and sinuses can act directly by localizing to the lungs. Alternatively, RV infection and allergen challenge may contribute to eosinophil influx into the airways, derived either from the bone marrow or locally from CD34+ve, IL5Ra+ precursors. Activated lymphocytes and eosinophil precursors, as well as newly generated bone marrow-derived eosinophils, express VLA-4 and, in the presence of pre-existing VCAM-I, will localize in the lung where they will exacerbate inflammation. Finally, we will demonstrate that CHS/NP is characterized by the dysregulation of cysLTs and their receptors. CysLTs promote eosinophil-mediated inflammation, mucous gland secretion, the proliferation of epithelium and endothelium, and they contribute to remodeling and fibrosis. We hypothesize that the modulation of cysLT production and activity by aspirin desensitization will attenuate CHS/NP.
| Platts-Mills, Thomas A E (2015) The allergy epidemics: 1870-2010. J Allergy Clin Immunol 136:3-13 |
| Steinke, John W; Platts-Mills, Thomas A E; Commins, Scott P (2015) The alpha-gal story: lessons learned from connecting the dots. J Allergy Clin Immunol 135:589-96; quiz 597 |
| Platts-Mills, Thomas A E; Schuyler, Alexander J; Tripathi, Anubha et al. (2015) Anaphylaxis to the carbohydrate side chain alpha-gal. Immunol Allergy Clin North Am 35:247-60 |
| Steinke, John W; Borish, Larry (2015) Factors driving the aspirin exacerbated respiratory disease phenotype. Am J Rhinol Allergy 29:35-40 |
| Steinke, John W; Negri, Julie; Liu, Lixia et al. (2014) Aspirin activation of eosinophils and mast cells: implications in the pathogenesis of aspirin-exacerbated respiratory disease. J Immunol 193:41-7 |
| Steinke, John W; Liu, Lixia; Huyett, Phillip et al. (2013) Prominent role of IFN-? in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 132:856-65.e1-3 |
| Payne, Spencer C; Early, S Brandon; Huyett, Phillip et al. (2011) Evidence for distinct histologic profile of nasal polyps with and without eosinophilia. Laryngoscope 121:2262-7 |
| Borish, Larry; Ayars, Andrew G; Kirkpatrick, Charles H (2011) Common variable immunodeficiency presenting as herpes simplex virus encephalitis. J Allergy Clin Immunol 127:541-3 |
| Laidlaw, Tanya M; Steinke, John W; Tinana, Adrienne M et al. (2011) Characterization of a novel human mast cell line that responds to stem cell factor and expresses functional FcýýRI. J Allergy Clin Immunol 127:815-22.e1-5 |
| Commins, Scott P; Borish, Larry; Steinke, John W (2010) Immunologic messenger molecules: cytokines, interferons, and chemokines. J Allergy Clin Immunol 125:S53-72 |
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